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1
McLennan, Geoffrey. "Oxygen toxicity and radiation injury to the pulmonary system." Title page, index and forward only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phm164.pdf.
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Bibliography: leaves 168-184. The work in this study encompasses oxygen free radical related inflammation in the peripheral lung and in lung cells. Animal and human studies have been used. Methods include cell culture with function studies, protein chemistry, animal and human physiology, and cell and lung structure through histopathology, and various forms of electron microscopy. The work resulting from this thesis has formed an important basis for understanding acute and chronic lung injury.
2
Corsino, Betsy Ann 1962. "THE PULMONARY RESPONSE INDUCED BY GLASS FIBERS (INFLAMMATION, SILICOSIS, MURINE MODEL)." Thesis, The University of Arizona, 1986. http://hdl.handle.net/10150/291468.
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Dokka, Sujatha. "IL-10 gene therapy for the treatment of pulmonary inflammation." Morgantown, W. Va. : [West Virginia University Libraries], 2000. http://etd.wvu.edu/templates/showETD.cfm?recnum=1421.
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Thesis (Ph. D.)--West Virginia University, 2000.<br>Title from document title page. Document formatted into pages; contains ix, 132 p. : ill. (some col.) Vita. Includes abstract. Includes bibliographical references.
4
Finlay, Alison. "Kinetics of pulmonary eosinophilia in a mouse model." Thesis, University of York, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245971.
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Karandashova, Sophia. "The Role of Ceramide in Neutrophil Elastase Induced Inflammation in the Lungs." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5468.
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Alterations to sphingolipid metabolism are associated with increased pulmonary inflammation, but the impact of inflammatory mediators, such as neutrophil elastase (NE), on airway sphingolipid homeostasis remains unknown. NE is a protease associated CF lung disease progression, and can be found in up to micromolar concentrations in patient airways. While sphingolipids have been investigated in the context of CF, the focus has been on loss of cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we present a novel observation: oropharyngeal aspiration of NE increases airway ceramides in mice. Using a previously characterized mouse model of NE-induced inflammation, we demonstrate that NE increases de novo ceramide production, which is likely mediated via increased SPTLC2 levels. Inhibition of de novo sphingolipid synthesis using myriocin, an SPT inhibitor, decreases airway ceramide as well as the release of pro-inflammatory signaling molecules induced by NE. Furthermore, in a retrospective study of the sphingolipid content of CF sputum—the largest of its type in this patient cohort to date, we investigated the association between NE and sphingolipids. There were linear correlations between the concentration of active NE and ceramide, sphingomyelin, and monohexosylceramide moieties as well as sphingosine-1-phosphate. The presence of Methicillin-resistant Staphylococcus aureus (MRSA) positive culture and female gender both strengthened the association of NE and sphingolipids, but higher FEV1 % predicted weakened the association, and Pseudomonas aeruginosa had no effect on the association between NE and sphingolipids. These data suggest that NE may increase sphingolipids in CF airways as it did in our in vivo model, and that this association is stronger in patients that have worse lung function, are female, and whose lungs are colonized with MRSA. Modulating sphingolipid homeostasis could provide novel pharmacological approaches for alleviating pulmonary inflammation.
6
McDaniel, Dylan K. "Characterization of Biomedical and Incidental Nanoparticles in the Lungs and Their Effects on Health." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/86128.
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Nanomaterials are defined as any material with at least one external dimension less than 100 nm. Recently, nanomaterials have become more common in medicine, technology, and engineering. One reason for their increased interest is due to nanomaterials having unique properties that allow them to interact effectively with biological systems. In terms of drug delivery, the lungs are a highly desirable site to administer therapeutic nanoparticles. Indeed, inflammatory diseases such as asthma and emphysema could potentially benefit from nanoparticle-mediated delivery. However, the lungs are also in constant contact with airborne particulate matter. Thus, harmful nanoparticles can enter the lungs and cause or even exacerbate inflammatory diseases. Our work focused on characterization of both therapeutic and potentially harmful nanoparticles in the lungs. We found that fluorescently-labeled nanoparticles were phagocytosed by macrophages and did not induce apoptosis or inflammation in the lungs, making them potentially useful as a therapeutic for inflammatory diseases. We also characterized a rare form of titanium-based particles called Magnéli phases, which have been shown to be produced via coal burning. We found that while these particles are non-inflammatory in the lungs of mice, they lead to apoptosis of macrophages as well as a change in gene expression associated with increased fibrosis. Ultimately, this was shown to lead to a decrease in lung function parameters and airway hyperresponsiveness, indicating increased lung stiffness after long-term nanoparticle exposure. Our data adds significant contributions to the field by assessing two nanoparticles with vastly different compositions in the lungs. Overall, we found that the unique properties of both particle types allows for interactions with cells and tissues. These interactions can have important outcomes on health, both in terms of disease treatment and exacerbation.<br>Ph. D.<br>Over the years, nanoparticles have become more common in medicine, technology, and engineering due to their unique properties. Many of these properties allow for increased interactions with biological materials. Organs such as the lungs are at increased risk of exposure because they naturally encounter microorganisms and airborne particles on a daily basis. However, the lungs are also a highly desirable site for drug delivery using nanoparticles, due to ease of access. Inflammatory diseases such as asthma and emphysema could potentially benefit from nanoparticle-mediated delivery. Additionally, harmful nanoparticles can enter the lungs and cause or even exacerbate these diseases. Unfortunately, there is a lack of knowledge pertaining to this subject. Our work focused on assessing the interactions of nanoparticles in the lungs. First, we looked at nanoparticles that could be used for drug delivery. We found that fluorescentlylabeled nanoparticles were taken up by phagocytic white blood cells called macrophages. Furthermore, these particles did not induce cell death or inflammation in the lungs. Therefore, we found that these particles could be useful for drug delivery in the lungs. Secondly, we investigated potentially harmful nanoparticles and their effects on the lungs. The titanium-based particles called Magnéli phases, have been shown to be produced through coal burning. We found that while these particles are non-inflammatory in the lungs, they do lead to programmed death of macrophages as well as the increase in genes associated with fibrosis. Ultimately these particles led to a decrease in lung function after long-term exposure.
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Zheng, Ling 1958. "Airway inflammation and remodelling post human lung transplantation." Monash University, Dept. of Medicine, 2002. http://arrow.monash.edu.au/hdl/1959.1/8099.
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Lewis, Joshua B. "Alterations in Tight Junctional Proteins and Their Effects on Pulmonary Inflammation." BYU ScholarsArchive, 2017. https://scholarsarchive.byu.edu/etd/6308.
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The lungs represent one of the earliest interfaces for pathogens and noxious stimuli to interact with the body. As such, careful maintenance of the permeability barrier is vital in providing homeostasis within the lung. Essential to maintaining this barrier is the tight junction, which primarily acts as a paracellular seal and regulator of ionic transport, but also contributes to establishing cell polarity, cell-to-cell integrity, and regulating cell proliferation and differentiation. The loss of these tight junctions has been documented to result in alterations in inflammation, and ultimately the development of many respiratory disorders such as COPD, Asthma, ARDS, and pulmonary fibrosis. One critical contributor that creates this permeability barrier is the tight junctional protein Claudin. While studies have begun to elucidate the various functions and roles of various Claudins, our understanding is still limited. To initially investigate these proteins, we looked at both temporal and spatial expression patterns for family members during development. A consistent pattern was demonstrated in mRNA expression for the majority of Claudin members. In general, Claudin expression underwent rapid increase during time periods that correlate with the pseudoglanduar/canalicular periods. One notable exception was Claudin 6 (Cldn6), which demonstrated decreasing levels of mRNA expression throughout gestation. We also sought to understand expression dynamics during the addition of maternal secondhand smoke (SHS) which resulted in an almost universal decrease in Claudin proteins. To more fully explore expression mechanisms that affect Claudin-6 (Cldn6), we exposed pulmonary alveolar type II (A549) cells to cigarette smoke extract (CSE) and found that it transcriptionally regulated Cldn6 expression. Using a luciferase reporter, we determined that transcription was negatively regulated at multiple promoter response elements by CSE, and transcription was equally hindered by hypoxic conditions. These findings identified Cldn6 as a potential target of SHS and other respiratory irritants such as diesel particulate matter (DPM). We next sought to assess whether an increase in Cldn6 was sufficient to provide a protective advantage against harmful exogenous exposure. To test this, we utilized a doxycycline induced Cldn6 over-expressing mouse, and subjected it to SHS for 30 days to stimulate an inflammatory state. Our findings demonstrated that Cldn6 transgenic animals have decreased inflammation as evidence by decreased total cell infiltration into the airways, decreased polymorphonuclocyte (PMNs) extravasation, total protein in bronchoalveolar lavage fluid (BALF), and decreased cytokine secretion. Anti-inflammatory advantages were also discovered during experiments involving acute exposure to DPM. In both cases, while stimulation of transgenic mice with SHS or DPM diminished Cldn6 expression, anti-inflammatory evidence emerged suggesting that genetic up-regulation of Cldn6 likely causes the recruitment of other tight junctional components during an organism's response to environmental assault.
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Lau, Kwok-wai, and 劉國威. "The involvement of serotoninergic system in cigarette smoke-induced oxidative stress and inflammation: relevantto chronic obstructive pulmonary disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47869616.
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Cigarette smoking is a major risk factor in the development of age-related
chronic obstructive pulmonary disease (COPD) with chronic airway inflammation
as a key feature. Currently, no effective treatment can reduce the protracted
inflammation in the lung of COPD. Further research on the inflammatory
mechanisms would therefore be important in determining new potential
therapeutic targets in COPD. Serotonin (5-hydroxytryptamine, 5-HT) is a
neurotransmitter that plays an important role in pulmonary functions and
inflammatory responses. The serotoninergic system including serotonin
transporter (SERT), serotonin receptors (5-HTR) and its metabolic enzyme
monoamine oxidase (MAO) have been reported to associate with cigarette
smoking and/or COPD. Blockade of serotonin receptor 2A (5-HTR2A) with its
selective antagonist ketanserin has been shown to improve lung function in COPD
patients. In this study, we hypothesize that the serotoninergic system is involved
in cigarette smoke-induced oxidative stress, inflammation and COPD.
Exposure to cigarette smoke medium (CSM) caused the elevation of
interleukin (IL)-8 levels in primary normal human bronchial epithelial (NHBE)
cells and a human bronchial epithelial cell line (BEAS-2B) in vitro via activation
of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling
pathway. Besides, CSM was found to disrupt the glutathione (GSH) system,
resulting in the translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2)
to the nucleus. Knock-down of Nrf2 by small interference RNA (siRNA) blocked
CSM-induced IL-8 release. Pretreatment with ketanserin was found to attenuate
CSM-induced IL-8 release by inhibiting the p38, ERK1/2, and Nrf2 signaling
pathways, and by partially restoring the GSH system. On the other hand, CSM
reduced MAO activity in BEAS-2B, indicating a reduced catabolism of 5-HT.
Furthermore, 5-HT was found to share the common p38 and ERK1/2 signaling
pathway with CSM in IL-8 release.
In the cigarette smoke-exposed rat model, the GSH system in the lung was
found to be disrupted compared to the sham-air control, supporting our in vitro
findings. Interestingly, we found an increased MAO-A activity in the lung of
cigarette smoke-exposed rats in comparison to sham air-exposed rats. The
increased MAO-A activity in the lung was associated with the reduction of 5-HT
levels in bronchoalveolar lavage (BAL) and lung homogenates, while the
increased metabolism of 5-HT may be involved in cigarette smoke-induced
superoxide anion levels. On the other hand, serum, but not plasma level of 5-HT
was elevated in cigarette smoke-exposed group, which may be due to platelet
activation caused by cigarette smoke.
In the clinical study, the elevated plasma 5-HT levels were found to be
associated with an increased odds ratio for COPD and positively correlated with
age in COPD patients. Furthermore, plasma 5-HT was also demonstrated to be a
significant mediator on the relation between cigarette smoking and COPD.
In summary, our study supports the hypothesis that the serotoninergic
system contributes to cigarette smoke-induced oxidative stress, inflammation and
COPD. The serotoninergic system (e.g. 5-HTR2A) may constitute potential
therapeutic targets for the treatment of COPD, which is worthy for further
investigation.<br>published_or_final_version<br>Medicine<br>Doctoral<br>Doctor of Philosophy
10
McNamara, Tracy Renee. "Chlamydia pneumoniae and airways inflammation : an investigation of the host cell-pathogen relationship /." Title page, table of contents and abstract only, 2004. http://web4.library.adelaide.edu.au/theses/09PH/09phm4791.pdf.
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Minucci, Sarah B. "Mathematical Models of the Inflammatory Response in the Lungs." VCU Scholars Compass, 2017. https://scholarscompass.vcu.edu/etd/5191.
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Inflammation in the lungs can occur for many reasons, from bacterial infections to stretch by mechanical ventilation. In this work we compare and contrast various mathematical models for lung injuries in the categories of acute infection, latent versus active infection, and particulate inhalation. We focus on systems of ordinary differential equations (ODEs), agent-based models (ABMs), and Boolean networks. Each type of model provides different insight into the immune response to damage in the lungs. This knowledge includes a better understanding of the complex dynamics of immune cells, proteins, and cytokines, recommendations for treatment with antibiotics, and a foundation for more well-informed experiments and clinical trials. In each chapter, we provide an in-depth analysis of one model and summaries of several others. In this way we gain a better understanding of the important aspects of modeling the immune response to lung injury and identify possible points for future research.
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Henry, Clémence. "Caractérisation du rôle du canal calcique TRPV4 dans la réponse inflammatoire pulmonaire : implication dans la mucoviscidose." Thesis, Tours, 2014. http://www.theses.fr/2014TOUR4037.
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La mucoviscidose est une maladie génétique dont l’atteinte respiratoire est responsable de 90 % de la morbidité et de la mortalité et est caractérisée par une infection chronique et une inflammation persistante. Cette inflammation non contrôlée participe de manière importante à la dégradation du tissu pulmonaire. Malgré les progrès récents, les thérapies actuelles ne permettent pas un traitement efficace de l’atteinte respiratoire. Il est donc indispensable d’identifier de nouveaux mécanismes moléculaires et cellulaires impliqués dans l’inflammation pulmonaire. Dans ce but, nous nous sommes intéressés au canal calcique "Transient Receptor Potential Vanilloid 4" (TRPV4) exprimé au niveau de l’épithélium respiratoire. A l’aide d’approches in vitro et in vivo, nous avons démontré que l’activation du TRPV4 déclenche la sécrétion de médiateurs inflammatoires cytokiniques et lipidiques et un recrutement leucocytaire dans les poumons. Nous avons également observé une altération de la signalisation dépendante du TRPV4 dans le contexte de la mucoviscidose, suggérant que le TRPV4 pourrait constituer une cible prometteuse pour le développement de nouvelles thérapies anti-inflammatoires applicables en santé respiratoire<br>Cystic fibrosis (CF) is due to mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). The pulmonary consequence of the disease accunts for over 90 % of the morbidity and mortality and is characterized by chronic infection and persistent inflammation. This uncontrolled inflammation participates significantly to the degradation of the lung tissue. Despite recent progress, current therapies do not allow effecgive treatment of CF lung disease. It is therefore necessary to characterize nex cellular and molecular mechanisms that could contribute to lung inflammation. In that purpose, we focused on the calcium channel "Transient Receptor Potential Vanilloid 4" (TRPV4) expressed by respiratory epithelium. Using in vitro and in vivo approaches, we found that TRP4 activation triggers the secretion of inflammatory mediators (including cytokines and lipids) and leukocytes recruitment into the lungs. We also observed a significant alteration of TRPV4-dependent signalling in the CF context, suggesting that TRPV4 could constitue a promising target for the development of new anti-inflammatory therapies in lung diseases such as CF
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Carroll, Mark. "A stereological study assessing the validity of using endobronchial biopsies to assess mast cell density in the central and peripheral bronchial tree." University of Western Australia. School of Medicine and Pharmacology, 2008. http://theses.library.uwa.edu.au/adt-WU2009.0005.
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[Tuncated abstract] There has been longstanding concern over whether endobronchial biopsies adequately represent inflammation throughout the bronchial tree in diseases such as asthma, despite the endobronchial biopsy technique having been used frequently to assess airway inflammation in research settings. There has also been ongoing debate about whether endobronchial biopsies should be assessed by new, unbiased, three-dimensional (3D) stereological techniques instead of traditional, two-dimensional (2D) non-stereological techniques. Therefore, the aims of this study were: (i) to investigate whether endobronchial biopsies represent the density of mast cells in the large and small airways, in alveolar walls and in the lung as a whole (ii) to use both stereological and non-stereological methods to address this question, and where possible, to compare the results of these two approaches. '...' Mast cell density in biopsies was not related to mast cell density immediately adjacent to the biopsy site or to mast cell density in the total airway wall in the large airways, the inner airway wall in the small airways, the walls of the alveoli or the lung as a whole. In general, measurements of mean mast cell density on biopsies to a depth of 100µm below the basement membrane were poorly related to mean mast cell density in other compartments of the lung. Mean 3D and 2D mast cell densities were strongly correlated (r 0.9, p < 0.005) and where both methods were used, results were similar. The mean height and area profile of a mast cell were approximately 12µm and 68µm2 respectively. In disk-shaped IUR lung samples, percent shrinkage in height due to paraffin processing was systematically greater than percent radial shrinkage by an average of approximately 4 times. Cavalieri lung volumes were systematically smaller than displacement volumes by an average of 14%. Any given endobronchial biopsy is unlikely to represent mast cell density around the airway wall generally in the vicinity of the biopsy site. However, the average of at least 4 biopsies from different sites in the proximal airways can be used to both represent mean mast cell density in the inner airway wall of the large airways, and act as the basis for inter-subject comparisons of mean mast cell density in the total airway wall of the small airways. On biopsies, mast cell counts should be measured over the entire inner airway wall not just to a depth of 100µm or less below the basement membrane. 3D mast cell densities obtained by stereological methods are closely related to 2D mast cell densities obtained by non-stereological methods and are likely to result in similar conclusions. Lung volumes are smaller when measured by the Cavalieri method than when measured by fluid displacement. Shrinkage of isotropic uniform random samples of human lung tissue due to paraffin processing is anisotropic. The mean volume of a mast cell in the human lung is likely to be much smaller than that reported previously for monkey lungs.
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Ruiz, Karina Fernandes. "Efeito do DMTI-II, um inibidor de Kunitz isolado das sementes de Dimorphandra molli na resposta inflamatória pulmonar alérgica em ratos." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308917.
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Orientador: Edson Antunes<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Medicas<br>Made available in DSpace on 2018-08-16T20:02:44Z (GMT). No. of bitstreams: 1
Ruiz_KarinaFernandes_M.pdf: 791032 bytes, checksum: 0730a107f795b476b046410752e6a5e3 (MD5)
Previous issue date: 2010<br>Resumo: DMTI-II é um inibidor de serinoproteinase do tipo Kunitz, isolado a partir das sementes de Dimorphandra mollis, uma árvore da família Leguminosae-Mimosoidea, com ampla distribuição nas regiões do cerrado brasileiro e popularmente conhecida por causar toxicidade em gados. Dados preliminares do nosso laboratório mostraram que DMTI-II causa um marcante influxo de eosinófilos após 4 horas de injeção, na cavidade peritoneal de ratos, um tempo no qual este tipo celular não é comumente observado com agentes inflamatórios clássicos. No sentido de ampliar nossos conhecimentos sobre o recrutamento eosinofílico em resposta ao DMTI-II, passamos a usar um modelo experimental no qual esta célula exerce papel fundamental, que é o de sensibilização e desafio com ovalbumina (OVA). O objetivo deste estudo é investigar os efeitos da exposição das vias áreas ao DMTI-II sobre o recrutamento de leucócitos para o pulmão de ratos sensibilizados e desafiados com OVA. Ratos Wistar foram sensibilizados através de injeção subcutânea de
OVA. Quatorze dias após, os ratos sensibilizados foram submetidos a instilações intranasais de DMTI-II (10 µg) ou PBS estéril (grupo controle). Após 2, 4 e 16 h de exposição ao DMTI-II, os animais foram desafiados com OVA. O lavado broncoalveolar (LBA), o sangue e a medula óssea foram coletados 24 horas após o desafio antigênico com OVA. Em grupo separado, os animais foram expostos ao DMTI-II 4 h após o desafio com OVA. De acordo com os resultados, a pré-exposição ao DMTI-II nos tempos de 4 e 16 h aumentou significativamente o recrutamento de eosinófilos no LBA de ratos desafiados com OVA. A pré-exposição de 2 e 4 h ao DMTI-II também promoveu aumento significativo do número de neutrófilos no LBA de ratos desafiados com OVA; entretanto, o número de células mononucleares não foi significativamente alterado. No sangue, a préexposição de 2 e 4 h ao DMTI-II aumentou significativamente o número de eosinófilos em ratos desafiados com OVA. Na medula óssea, a pré-exposição de 4 e 16 h ao DMTI-II, isoladamente, aumentou de forma significativa o número de eosinófilos, sendo esse aumento potencializado em ratos desafiados com OVA no tempo de 4h. A pós-exposição ao DMTI-II aumentou o número de eosinófilos e neutrófilos no LBA e no sangue de ratos desafiados com OVA. Além disso, o número de eosinófilos foi superior quando comparado ao protocolo de pré-exposição. Por outro lado, a pós-exposição ao DMTI-II não afetou o número de eosinófilos na medula óssea de animais desafiados com OVA. No LBA ou soro de ratos desafiados com OVA, notamos uma elevação significativa nos níveis de IgE, IL-4, eotaxina e LTB4. Porém, a exposição ao DMTI-II elevou somente os níveis de IL-4 nos animais desafiados com OVA. A pré- e pós-exposição das vias aéreas ao DMTI-II exacerba a inflamação pulmonar alérgica, com aumento do influxo de células polimorfonucleares. A capacidade do DMTI-II em recrutar eosinófilos está associada, provavelmente àspropriedades alérgicas dos inibidores de proteinases do tipo Kunitz.<br>Abstract: DMTI-II is a Kunitz-type serine proteinase inhibitor isolated from the seeds of Dimorphandra mollis, a widespread Leguminosae-Mimosoidea tree found in the savannahlike ecosystem, popularly known in Brazil to be toxic to cattle. Preliminary date in our laboratory showed that DMTI-II causes a marked eosinophil influx into the rat peritoneal cavity as early as 4 h after injection, a time by which no such cells are usually seen with classical inflammatory agents. In order to further explore our understanding about the eosinophil recruitment in response to DMTI-II we have moved to an experimental model where this cell type exhibits a central role, that is, the sensitization and challenge of rats with ovalbumin (OVA). Therefore, this study aimed to investigate the OVA-induced pulmonary cell recruitment in OVA-sensitized rats exposed to DMTI-II. Male Wistar rats were sensitized by subcutaneous injection of OVA. Fourteen day later, sensitized rats were submitted to intranasal instillations of DMTI-II (10 µg) or sterile PBS buffer (control group). At 2, 4 and 16 h after DMTI-II exposure, animals were challenged with OVA (or instilled with PBS). Bronchoalveolar lavage (BAL) fluid, bone marrow and blood were obtained at 24 h after OVA challenge. In a separate group of animals, rats were exposed to DMTI-II at 4 h after OVA challenge. Pre-exposure to DMTI-II 4 and 16 h prior to OVA-challenged markedly enhanced the eosinophil counts in BAL fluid in OVA-challenged rats. Pre-exposure to DMTI-II at 2 and 4 h prior to OVA-challenged markedly enhanced the neutrophil counts in BAL fluid in OVA-challenged rats, whereas mononuclear cell counts remained unchanged. Pre-exposure to DMTI-II at 2 and 4 h prior to OVA-challenged markedly enhanced the eosinophil counts in circulating blood in OVA-challenged rats. In bone marrow, pre-exposure to DMTI-II alone, 4 and 16 h prior OVA-challenged, significantly increased the number of eosinophils, and that was further increased in OVAchallenged rats 4 h prior to OVA-challenged. Similarly to the pre-exposure protocols, postexposure to DMTI-II elevated the eosinophil e neutrophil counts in BAL fluid and blood when compared with control group. In bone marrow, post-exposure to DMTI-II did not affect the number of eosinophils. In OVA-challenged rats, the levels of IgE in serum and of IL-4, eotaxin and LTB4 in BAL fluid were significantly higher compared with nonchallenged animals. Pre-exposure to DMTI-II alone elevated the IL-4 levels, and further elevated this cytokine levels in OVA-challenged rats. The increased IgE, eotaxin and LTB4 seen in OVA-challenged rats remained unchanged in animals pre-exposed to DMTI-II. In conclusion, the airways exposure to DMTI-II exacerbate the allergic pulmonary polymorphonuclear cell influx. This capacity of DMTI-II to recruit eosinophils is likely to reflect the allergen properties of proteinase inhibitors belonging to the Kunitz family.<br>Mestrado<br>Mestre em Farmacologia
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Vanderstocken, Gilles. "Caractérisation du rôle des nucléotides extracellulaires et du récepteur purinergique P2Y2 dans la physiopathologie des maladies pulmonaires inflammatoires." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209591.
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Amongst respiratory diseases, inflammatory lung diseases constitute a major part of public <p>health problem. As a consequence, investigating the immune mechanisms that contribute to <p>the pathogenesis of these diseases is essential to identify candidate targets for the <p>development of new therapeutic drugs. Furthermore, over the past 20 years, the growing awareness <p>that purinergic signalling events shape the immune and inflammatory responses to infection and <p>allergic reactions warranted the development of animal models to assess their importance in vivo in <p>acute lung injury and chronic airway diseases. The field of purinergic inflammation formulated the <p>unifying concept that ATP is released as a «danger signal» to induce inflammatory responses upon <p>binding purinergic receptors.<p>According to these elements, we began in 2007 to evaluate lung inflammation in mice deficient for <p>the P2Y2 purinergic receptor in TH2 and TH1 models. The most convincing evidence that the P2Y2<p>receptor is engaged during alarm situations comes from studies related to cystic fibrosis and asthma. <p>Indeed, chronic respiratory diseases are commonly associated with elevated airway ATP <p>concentrations, as reported in cystic fibrosis, but also in idiopathic pulmonary fibrosis and chronic <p>obstructive pulmonary disease (COPD) patients, and they are raised by allergens in asthmatic <p>patients.<p>First, we demonstrated a significant role of the P2Y2R in a TH2-ovalbumin(OVA)-induced asthma <p>model. We observed that eosinophil accumulation, a distinctive feature of lung allergic inflammation, <p>was defective in OVA-treated P2Y2-deficient mice compared with OVA-treated wild type animals. <p>Interestingly, the upregulation of VCAM-1 was lower on lung endothelial cells of OVA-treated P2Y2 <p>knockout mice compared with OVA-treated wild type animals. Adhesion assays demonstrated that <p>the action of UTP on leukocyte adhesion through the regulation of endothelial VCAM-1 was <p>abolished in P2Y2-deficient lung endothelial cells. Additionally, the level of soluble VCAM-1, reported <p>as an inducer of eosinophil chemotaxis, was strongly reduced in the bronchoalveolar lavage fluid of <p>P2Y2-deficient mice.<p>Secondly, we studied the consequences of P2Y2R loss in lung inflammation initiated after pneumonia <p>virus of mice (PVM) infection in collaboration with the group of Pr. Daniel Desmecht (ULg). We <p>demonstrated here that P2Y2<p>-/-<p>mice display a severe increase in morbidity and mortality rate in <p>response to PVM. Lower survival of P2Y2<p>-/-<p>mice was not correlated with excessive inflammation <p>despite the higher level of neutrophil recruiters in their broncho-alveolar fluids. Interestingly, we <p>observed lower numbers of dendritic cells, CD4<p>+<p>T cells and CD8<p>+<p>T cells in P2Y2<p>-/-<p>mice compared to <p>P2Y2<p>+/+<p>infected lungs. Lower level of IL-12 and higher level of IL-6 in broncho-alveolar fluid support <p>an inhibition of Th1 response in P2Y2<p>-/-<p>mice. Quantification of DC recruiter expression revealed <p>comparable IP-10 and MIP-3&<br>Doctorat en Sciences biomédicales et pharmaceutiques<br>info:eu-repo/semantics/nonPublished
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Cooper, Racheal L. "An Applied Mathematics Approach to Modeling Inflammation: Hematopoietic Bone Marrow Stem Cells, Systemic Estrogen and Wound Healing and Gas Exchange in the Lungs and Body." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4312.
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Mathematical models apply to a multitude physiological processes and are used to make predictions and analyze outcomes of these processes. Specifically, in the medical field, a mathematical model uses a set of initial conditions that represents a physiological state as input and a set of parameter values are used to describe the interaction between variables being modeled. These models are used to analyze possible outcomes, and assist physicians in choosing the most appropriate treatment options for a particular situation. We aim to use mathematical modeling to analyze the dynamics of processes involved in the inflammatory process.
First, we create a model of hematopoiesis, the processes of creating new blood cells. We analyze stem cell collection regimens and statistically sample parameter space in order to create a model accounts for the dynamics of multiple patients. Next, we modify an existing model of the wound healing response by introducing a variable for two inflammatory cell types. We analyze the timing of the inflammatory response and introduce the presence of systemic estrogen in the model, as there is evidence that the presence of estrogen leads to a more efficient wound healing response. Last, we mathematically model the gas exchange process in the lungs and body in order to lay the foundation for a model of the inflammatory response in the lung under conditions of mechanical ventilation. We introduce normal and ventilation breathing waveforms and a third state of hemoglobin in a closed loop partial differential equations model. We account for gas exchange in the lung and body compartments in addition to introducing a third discretized well-mixing compartment between the two.
We use ordinary and partial differential equations to model these systems over one or more independent variables, as well as classical analysis techniques and computational methods to analyze systems. Statistical sampling is also used to investigate parameter values in order for the mathematical models developed to account for patient-to-patient variability. This alters the traditional mathematical model, which yields a single set of parameter values that represent one instance of the physiology, into a mathematical model that accounts for many different instances of physiology.}
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Marwick, John Alexander. "The impact of cigarette smoke on cell survival and inflammation in rat lungs : the role of oxidative stress and VEGF/KDR signalling and its implications in COPD." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/24912.
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A decrease in both VEGF and KDR was observed in rat lungs exposed to cigarette smoke as well as disruption to the other components of their signalling complex, neurophilin-1 and glycpican-1. Impaired survival signalling in rat lungs exposed to cigarette smoke was also demonstrated. These changes were mirrored in both smokers and COPD lungs, indicating that these changes may play a role in cigarette smoke induced COPD. Cigarette smoke-triggered inflammation in COPD may be maintained by a mechanism involving enhanced pro-inflammatory gene transcription. The balance between histone acetylation and deacetylation is a key regulator of the specificity and duration of gene transcription, where an imbalance may result in excessive transcription of specific pro-inflammatory genes in the lungs. Cigarette smoke exposure was shown to result in an influx of inflammatory cells and chromatin remodelling in rat lungs. This was associated with an increase in histone acetylation concomitant with increased mitogen activated protein kinase activation and increased DNA binding of pro-inflammatory transcription factors. Reduced histone deacetylase 2 expression and activity was observed, which may be a result of covalent modification. These findings suggest a plausible molecular mechanism by which cigarette smoke drives pro-inflammatory gene transcription and an inflammatory response in the lungs by oxidative stress activated pathways.
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Fallata, Ghaith Mohammed. "Association of gut luminal metabolites and allergic responses." Wright State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=wright1515185113264117.
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Saleh, Yara. "Etude de la pathogénicité pulmonaire des polluants atmosphériques nanoparticulaires." Thesis, Lille 2, 2019. http://www.theses.fr/2019LIL2S014.
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Introduction : Des études épidémiologiques montrent que les polluants atmosphériques particulaires augmentent le risque de morbidité et de mortalité liées à des maladies respiratoires. La toxicité des particules dépend de leur composition chimique, leur conférant des propriétés mutagènes et/ou cancérogènes, mais également de leur granulométrie qui va conditionner leur pénétration et rétention dans les voies respiratoires.Les particules fines (PF<2,5μm) et surtout les particules ultrafines (PUF<0,1μm) peuvent ainsi atteindre les voies aériennes les plus profondes où leur épuration s’effectuera lentement par clairance macrophagique. Bien que les PUF possèdent une réactivité de surface et donc une toxicité potentielle plus élevées que les PF, leur impact toxicologique réel reste à déterminer.Matériels et méthodes : Pour ce projet, nous avons comparé l’impact sur la santé respiratoire d’une exposition prolongée à des PF et PUF collectées sur un même site urbano-industriel. Après caractérisation physico-chimique des particules (granulométrie, composition surfacique, élémentaire, en HAP), nous avons exposé des souris BALB/c par voie intranasale de manière aiguë à des doses uniques croissantes de PF ou de PUF (10, 50 ou 100 μg) et de manière subchronique pendant 1 mois ou 3 mois, à raison de 3 doses de 10 μg de particules par semaine. Les souris ont été ensuite sacrifiées, des lavages broncho-alvéolaires (LBA) ont été réalisés et différents tissus (sang, poumons, foie, fémurs) ont été prélevés pour effectuer des analyses toxicologiques.Résultats : La composition chimique élémentaire des PF et PUF n’a pas montré de différences majeures mais atteste leur origine industrielle par leur richesse en certains métaux. Par ailleurs, une teneur légèrement supérieure en HAP a été détectée dans les PF par rapport aux PUF. Pour toutes les conditions expérimentales, aucun effet génotoxique et/ou mutagène in vivo n’a été mis en évidence (tests des comètes, des micronoyaux, Pig-A négatifs). En revanche, l’étude de la cellularité des LBA, la quantification de l’expression génique des cytokines et l’analyse histologique des tissus pulmonaires suggèrent la survenue d’une inflammation chronique chez les souris exposées. L’apparition de zones lésionnelles étendues3est cependant plus précoce et plus marquée dans les poumons des souris exposées aux PUF. Des analyses transcriptomiques ont montré d’une part que le nombre de gènes dérégulés croît avec la dose et le temps d’exposition, et d’autre part que ce nombre est largement supérieur chez les souris exposées aux PUF par rapport à celles exposées aux PF. L’identification des principales voies de signalisation les plus significativement impactées confirme que les PUF induisent une réponse des tissus pulmonaires plus intense et plus précoce que les PF.En ce qui concerne les études épigénétiques, une dérégulation de la méthylation de l’ADN, des modifications d’histones et de l’expression génique de certains miARN était plus prononcée chez les souris exposées aux PUF. L’analyse fonctionnelle en cours des miARN spécifiquement dérégulés par les PUF, ou dérégulés communément par les PUF et les PF, devrait permettre l’identification de leurs ARNm cibles.Conclusion : Les résultats issus de ce projet suggèrent que les PUF ont un impact plus nocif sur la santé respiratoire que les PF, et devraient permettre l’identification de nouveaux biomarqueurs d’atteintes tissulaires. Les informations issues de ce projet pourront être transmises aux différents organismes en charge des polluants atmosphériques et de leurs effets sur la santé [...]<br>Background: Air pollution is one of the leading causes of premature death worldwide. Among air pollutants, particulate matter (PM) is a major health risk factor, through the development of pulmonary diseases. The toxicity of PM depends on their chemical composition and size which increases their mutagenic and/or carcinogenic properties and determine their penetration and retention in the respiratory tract. Fine particles (FP <2,5μm) and ultrafine particles (UFP <0,1μm) can thus reach the deepest airways where their purification will be carried out slowly by macrophage clearance. Compared to FP, less is known about the toxicological impact of UFP.Methods: We first compared the impact of prolonged exposure to PF and PUF collected on the same urban-industrial site on the respiratory health in mice. After physicochemical characterization of the particles (granulometry, surface composition, elementary composition, PAH), BALB/c mice were intranasally exposed to increasing single doses of PF or PUF (10, 50 or 100 μg) and subchronically for 1 month or 3 months, to 3 doses of 10 μg of particles per week. Mice were then sacrificed, bronchoalveolar lavages (BAL) were performed and different samples (blood, lungs, liver, femurs) were taken for toxicological analyses.Results: The elemental chemical composition of FP and UFP did not show any major differences but highlights their industrial origin due to their high content of metals. On the other hand, a slightly higher PAH content was detected in FP compared to PUF. For all experimental conditions, no in vivo genotoxic and / or mutagenic effects were detected (comet, micronucleus, Pig-A negative tests). However, the study of the cellularity of BAL, the quantification of cytokine gene expression and histological analysis of lung tissue suggest the occurrence of chronic inflammation in exposed mice lungs. More extended lesioned areas were, however, observed in the UFP-exposed mice. Transcriptomic analyses have shown, on the one hand, that the number of deregulated genes increases with the dose and the time of exposure, and on the other hand that this number is much higher in mice exposed to UFP compared to those exposed to FP. The identification of the main signalling pathways most5significantly impacted confirms that UFP induce greater and earlier lung tissue response than PF. Concerning the epigenetic analyses, deregulation of DNA methylation, histone modifications, and gene expression of some miRNAs was more pronounced in PUF-exposed mice. The ongoing functional analysis of miRNAs specifically deregulated by PUFs, or commonly deregulated by PUFs and PFs, should allow the identification of their target mRNAs.Conclusion: The results of this study suggest that UFP have greater impact on the respiratory system than FPs which would allow the identification of new biomarkers of tissue damage. The information resulting from this project can be transmitted to the different organizations in charge of air pollutants and their effects on health, to the concerned authorities and to the industries in order to contribute to make better decisions regarding the reduction of emissions of particulate pollutants of greatest concern. They will thus help to update the current regulations in order to include UFP and limit their emissions
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Haegens, Astrid. "Role of Myeloperoxidase in lung inflammation." Maastricht : Maastricht : [Maastricht University] ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=11652.
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Nelson, Kevin Joseph. "MICRORNA REGULATION OF VENTILATOR INDUCED LUNG INJURY AND PRESSURE-INDUCED LUNG INFLAMMATION." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1462276463.
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Shoemark, Amelia. "Non invasive measurement of lung inflammation in bronchiectasis." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509803.
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Lai, Cheryl Chuk-Ke. "Therapeutic manipulation of inflammation in exacerbated lung disease." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/61486.
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It is well known that existing and prior inflammatory events in the lung can adversely affect subsequent inflammatory events even though the inciting antigen might be different. For example, viral infections can enhance secondary bacterial infections and also the symptoms of asthma causing increased morbidity and mortality. Understanding changes in the lung micro-environment that lead to altered lung responsiveness is important given the increasing incidence in allergic diseases and the emergence of pandemic influenza strains. Elucidating the molecular mechanisms of these prolonged alterations could lead to new therapeutic strategies. Susceptibility to bacterial super-infections has been attributed to reduced toll-like receptor (TLR) responses in the inflammation-experienced lung. The triggering receptor expressed on myeloid cells (TREM) family of innate immune receptors fine-tune TLR responses, but have yet to be studied in the context of influenza and secondary bacterial infection. Targeting specific immune signalling receptors or signalling kinases involved in the inflammatory process in the lung by use of inhaled drugs could provide specific treatment of inflammatory lung diseases minimising effects in other organs or tissues. The aim of this thesis was to investigate the role of TREMs during influenza and secondary bacterial infection and to determine the effects of inhaled signalling kinase inhibitors in models of viral exacerbations of allergic inflammation. TREM-2 expression was shown to be upregulated during the peak of influenza-induced inflammation. Furthermore, soluble (s)TREM-1 in bronchoalveolar lavage (BAL), lung and serum coincide with heightened susceptibility to bacterial infection post-influenza virus. These novel findings suggest that targeted manipulation of TREM-1 (or prevention of its cleavage into the soluble form) and TREM-2 has the potential to restore the inflammatory tone of the airspaces to prevent subsequent infectious complications. Narrow-spectrum signalling kinase inhibitor TC2 reduced BAL eosinophils and total and allergen-specific serum IgE production in house dust mite (HDM)-induced allergic inflammation. Furthermore, a new model of viral infection during HDM-induced allergic inflammation was developed. Surprisingly, exposure to HDM prior to respiratory syncytial virus (RSV) infection led to reduced RSV-induced weight loss, damage and proinflammatory mediator release, which correlated with increased TREM-2 expression in the early stages of infection. Treatment with the kinase inhibitor TC2 during viral infection in allergen-exposed mice, however, still reduced airway hyperesponsiveness. Thus, whether severe asthma is characterised by additive inflammatory conditions or exacerbation of an underlying problem by infection, kinase inhibitors still hold promise in the clinic.
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Farghaly, Hanan. "Pharmacological targets for gene therapy in lung inflammation." Thesis, University of Bath, 2008. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500756.
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Interleukin-13 (IL-13) has been implicated as a critical inducer of a number of features of allergy and asthma including the induction of nonspecific airway hyperresponsiveness (AHR), eosinophilic inflammatory response, eotaxin production, excess mucus formation, and fibrosis. Determining the mechanism(s) of AHR, a hallmark of asthma, is crucial to our understanding of both the pathogenesis and successful treatment of asthma. After carrying out initial experiments to determine the effect of IL-13-induced AHR on murine and rat tracheal rings, mice tissues were chosen for subsequent experiments due to their consistent results and the fact that the mouse genetic map was completed in 1996, which will enable subsequent gene therapy work. Human and mouse share a high percentage of their genes with an average of 85% homology. Numerous IL-13 signalling studies have concentrated on the JAK/STAT6 pathway. IL-13 also activates phosphoinositide 3-kinase (PI3K) and downstream effector molecules. In experiments presented in this thesis pharmacological and genetic approaches implicate the involvement of PI3K and its individual isoform PI3Kδ in IL-13 induced AHR in vitro and this involvement was confirmed using a small interference RNA (siRNA) technology approach. However, IL-13 induced an early activation of PI3K, whereas increased responsiveness was not observed until overnight incubation. Arginase I induction was demonstrated to be another PI3K-dependent potential mechanism of IL-13-induced hyperresponsiveness. The epithelium is also implicated in IL-13-induced hyperresponsiveness, however, the induction of arginase I was demonstrated in both intact and denuded epithelium tracheal rings. The siRNA approach was also employed in 9HTEo-, A549 and BEAS-2B cell lines using different transfecting agents. From these findings, it is concluded that class IA p110δ could be a useful target for the treatment of asthma by preventing IL-13-induced airway smooth muscle hyperresponsiveness and also that arginase I may be involved in IL-13-induced hyperresponsiveness through PI3K- and epithelial-dependent pathways.
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Rodriguez, Ihsan. "Well-being and Inflammation in Interstitial Lung Disease." The Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1619031719578262.
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Larsson, Emelie Olivia. "Immune to brain communication in allergic lung inflammation." Thesis, University of Southampton, 2013. https://eprints.soton.ac.uk/355709/.
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Asthma, a chronic TH2-mediated inflammatory disease of the airways, is the most common form of allergy in the Western world, affecting 300 million people worldwide. Epidemiological studies have shown that asthma is associated with mood disorders, such as anxiety and depression, and numerous experiments have reported that asthma induces functional changes in neuronal fibres of the peripheral nervous system (PNS), which innervate the brain. It is unknown, however, how allergic lung inflammation impacts on the central nervous system (CNS). The ability for peripheral inflammation to impact on the brain, altering behaviour and neuronal activity in the CNS, is a well-recognised and physiological phenomenon, known as immune to brain communication, but has, until now, only focused on how innate pro-inflammatory and TH1, but not TH2, type immune responses impact on the brain. Critically, immunomodulatory therapeutics, which involve stimulation of an innate pro-inflammatory immune response, are currently being developed for the treatment of asthma, highlighting the importance of understanding the effect of allergic lung inflammation and its treatment on the brain. Consequently, using acute and chronic localised TH2 models of inflammation, we investigated how allergic lung inflammation impacted on the CNS and subsequently determined the secondary impact of immunomodulation with the Toll-like receptor 7 (TLR7) agonist resiquimod. Acute TH2 inflammation in the peritoneum and lung was found to communicate with the brain, via a vagal route of communication. Crucially, it led to a distinct pattern of neuronal activity, with no changes in sickness behaviour or CNS inflammation, changes widely different to those known to occur following systemic TH1 inflammation. At chronic stages of lung inflammation, changes in genes associated with synaptic plasticity in the brainstem and altered expression of the GABAB receptor and brain-derived neurotrophic factor in the hippocampus were observed, firstly providing a CNS-dependent biological explanation for airway hyperresponsiveness, a critical pathological symptom of asthma, and secondly offering a biological justification for the prevalence of mood disorders in asthmatic patients. Resiquimod treatment in allergic animals was associated with attenuated central inflammatory responses, as compared to treatment in healthy animals, encouraging and reassuring in terms of patient well-being and, critically, also insinuating that safety of therapeutics differs in diseased, as opposed to healthy individuals. The results in this thesis are some of the first to identify that physiological inflammatory diseases impact on the CNS, highlighting the importance of immune to brain communication on pathological and psychopathological symptoms of a disease, and additionally demonstrating how inflammatory conditions can modify the off-target effects of a drug. Not only do these results provide a foundation for the future of immune to brain communication research, namely understanding how physiological inflammatory diseases impact on the CNS, but also have the potential to be translational and emulated in a clinical setting.
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Blohmke, Christoph Johannes. "Innate immunity and inflammation in cystic fibrosis lung disease." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/34559.
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Inflammatory lung disease is the major life-limiting factor of cystic fibrosis (CF) and occurs through a self-sustaining cycle of airway obstruction, infection and inflammation. Although there is no consensus regarding the pathways responsible for the excessive inflammation, reducing lung-damaging pro-inflammatory responses are likely to be beneficial for CF patients. Using CF (IB3-1) and non-CF control (C38) respiratory cells, the host-pathogen interaction between the airway epithelium and the common CF pathogens P. aeruginosa and B. cepacia was investigated. Using purified Toll-like receptor (TLR) ligands and different knock-out strains of P. aeruginosa, TLR5 was identified as the receptor mediating much of the increased inflammatory response to CF pathogens. To validate TLR5 as an anti-inflammatory target, the disease modifying effects of the functionally relevant TLR5 c.1174C>T single nucleotide polymorphism (rs5744168) was analysed in approximately 80% of Canada’s CF population. rs5744168 encodes a premature stop codon and the T allele is associated with 45.5 – 76.3% reduction in flagellin responsiveness. CF patients carrying rs5744168 (CT or TT) had a significantly higher body mass index than CF patients homozygous for the common allele (CC) (p=0.044); however, similar improvements in lung function associated with the T allele were not statistically significant. Since TLR5 mediates much of the excessive inflammation to P. aeruginosa, it is of interest to understand the mechanisms underlying this dysregulated immune response. By combining gene expression arrays with network analyses and biochemical assays, ER stress was identified as a potential mechanism dysregulating p38 MAP kinase activity and leading to potentiated immune responses. Together, this thesis provides data underscoring the importance of TLR5-mediated excessive pro-inflammatory immune response by CF airway cells to P. aeruginosa. The association of the TLR5392STOP SNP with higher BMI in adult CF patients indicates an important role for TLR5 in CF disease severity. Finally, ER stress may potentiate the immune response to flagellin by signalling through p38 MAP kinase, supporting an emerging paradigm in which the imbalance of protein homeostasis can lead to altered signalling events. Strategies to inhibit either TLR5 signalling, ER stress signalling or to improve the cellular protein homeostasis may prove useful in treating life limiting inflammation in CF.
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McClean, K. M. "Nutrition, Inflammation and Lung Function in Middle-Aged Men." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.527847.
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Clayton, Andrew Alan. "Linking lung inflammation and chloride secretion in cystic fibrosis." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433982.
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Phillips, Gary John. "The role of inflammation in hyperoxia-induced lung injury." Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295865.
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Sundaram, Kruthika. "Expression And Function Of Human IkappaBzeta In Lung Inflammation." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1436224271.
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Lyonga, Daphne E. "The regulation of lung homeostasis and influenza-associated inflammation." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/7127.
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Alveolar macrophages are the main cell population in the naïve airway and are held in a state of tight regulation by several suppressive mechanisms. One would expect them to display a regulatory phenotype but here we show that at homeostasis they express markers of alternative activation such as YM1 and mannose receptor (MR) but not resistin-like molecule (RELM)-α. We show also that these markers are differentially regulated during influenza infection on macrophage populations in the lungs and airways. We hypothesised that removing the suppressive effects of IL-10 using an IL-10R blocking antibody would alter alveolar macrophage phenotype and the immune response to influenza infection. We now demonstrate that IL-10R blockade does not significantly alter the phenotype of alveolar macrophages at homeostasis but does increase in their numbers and infiltrate of monocyte/macrophages and T cells into the airways during a subsequent influenza infection. Blockade of the interaction between the co-stimulatory molecule GITR and its ligand GITRL is beneficial for disease outcome in mouse models of chronic lung inflammation; therefore we hypothesised that it may also abrogate influenza-associated immune pathology. We now show that GITR and GITRL are differentially expressed in the lungs and airways during influenza infection; however contrary to expectations, blockade of the interaction between the two accelerated influenza-induced weight loss and lung cellularity. This may indicate a novel regulatory role for GITRL in influenza-induced inflammation. This thesis shows that alveolar macrophages represent an atypical alternatively activated macrophage population, whose phenotype is not altered by IL-10R blockade. However, we show that prior IL-10R blockade can alter the immune response to subsequent influenza infection, and blockade of GITRL during influenza infection may be detrimental for the outcome of influenza infection.
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Lucas, Christopher David. "Modulation of inflammatory cell apoptosis in infection-associated inflammation." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17874.
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Neutrophils are a central component of the innate immune system, whose major role is to defend the host against invading microorganisms. As such they are integral players in the process of inflammation, the response of vascular tissues to injury. They are frequently the first immune cells recruited from the systemic circulation into a site of tissue injury or infection where they themselves play a key antimicrobial role. Direct killing of microbes can be accomplished by phagocytosis, degranulation, production of reactive oxygen species (ROS) or the release of DNA and antimicrobial peptides into the extracellular milieu (NETosis). In addition neutrophils orchestrate the recruitment and activation of other leucocytes, further contributing to host defence. The central importance of neutrophils in immunity is revealed by defects in either number or function leading to recurrent life threatening infection. However, as the toxic arsenal of neutrophil constituents lack specificity they can also be damaging to surrounding host tissues causing exacerbated inflammation. It is therefore essential that neutrophil function is tightly controlled to allow an appropriate response to be mounted against invading pathogens while simultaneously minimising host tissue injury. Therefore, once the inciting inflammatory insult has been successfully cleared or controlled it is imperative that these non-tissue resident specialised immune cells are rapidly ‘switched off’ or cleared to allow the return to homeostasis. This resolution phase of the inflammatory cascade is now recognised as an energy dependent, finely controlled endogenous process, the beginnings of which are activated at the onset of inflammation. One of the main aims of resolution is to ensure efficient clearance of leucocytes that are no longer necessary. It is likely that a major clearance route is by the highly regulated and energy dependent processes of neutrophil programmed cell death (apoptosis) with subsequent uptake and disposal of apoptotic neutrophils by tissue macrophages. This process of neutrophil apoptosis renders the neutrophils nonfunctional and preserves cell membrane integrity, thus preventing further release of histotoxic neutrophil-derived inflammatory mediators into the extracellular environment. Furthermore, the recognition, uptake and disposal of apoptotic neutrophils cause a dynamic change in the phagocytosing macrophage phenotype with alterations in inflammatory mediator production. The fundamental importance of neutrophil apoptosis and subsequent efferocytosis in inflammation resolution is highlighted by the pathological consequences of neutrophil necrosis or failed apoptotic cell clearance, which leads to enhanced tissue injury and autoimmunity. Acute lung infection (pneumonia) is a common and serious condition affecting both developed and developing countries; globally, childhood pneumonia is the leading cause of death in children aged less than 5 years and pneumonia is the most common fatal infection in the developed world. In over half of patients with community acquired pneumonia no causative organism is ever isolated suggesting that although the immune response has successfully controlled infection, continued uncontrolled neutrophilic inflammation in the lung continues to cause morbidity and mortality. Indeed, pneumonia frequently progresses to acute respiratory distress syndrome (ARDS), a devastating acute inflammatory condition of the lungs characterized by inflammatory cell recruitment and accumulation of protein rich oedema fluid leading to impaired lung function. ARDS affects 200,000 critically ill patients in the USA per year, and has a substantial mortality rate of up to 40%. Despite advances in intensive care treatment and antimicrobial therapy mortality from pneumonia has not fallen since the 1950s, and at present there are no specific therapies for infection-related lung inflammation or ARDS. Understanding the mechanism behind such uncontrolled, persisting inflammation, and the need for novel approaches to target infection related lung injury are therefore both urgent and essential. This thesis examines the potential of neutrophil apoptosis-inducing pharmacological agents as potential treatments for infection-associated lung inflammation. The primary agents used include a cyclin-dependent kinase inhibitor as well as plant-derived polyphenolic flavones. The ability of these compounds to induce human neutrophil apoptosis in vitro, the key importance of the intracellular neutrophil survival protein Mcl-1 in mediating this process, and the effect of targeting Mcl-1 in human macrophages is investigated. In addition, neutrophilic inflammation is modelled in zebrafish and mice with both sterile and bacterial-driven models of inflammation. A key role for Mcl-1 is delineated in vivo, with it acting as an endogenous controller of the innate immune response by influencing neutrophil apoptosis, but without effects on macrophage apoptosis or ability to phagocytose apoptotic cells. Driving neutrophil apoptosis by down-regulation of Mcl-1 accelerates resolution of inflammation in vivo. This therapeutic approach is also found to have indirect anti-bacterial effects in a model of E. Coli induced pneumonia, in stark contrast to established anti-inflammatory approaches which routinely cause immune paresis and life threatening infection. As such, targeting inflammatory cell apoptosis by changes in Mcl-1 offers a potential new therapeutic approach for the treatment of infection-associated inflammation.
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Pariollaud, Marie. "Role of REV-ERBα in the regulation of lung inflammation". Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/role-of-reverbalpha-in-the-regulation-of-lung-inflammation(140db598-4670-4605-8c8e-f589fec33e69).html.
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The clock-controlled nuclear receptor REV-ERBα has emerged as a critical regulator of multiple pathways involved in metabolism, development and immunity. Recent evidence has highlighted a major role for the clock in epithelial cells regulating lung inflammation, mediated by control of neutrophil chemokine expression. In this thesis, I examined the role of REV-ERBα in pulmonary immunity, using in-vivo gene targeting and nebulised lipopolysaccharide (LPS), a model for gram-negative bacterial infection, ex-vivo cell biology approaches and in vitro cell models. Initial studies of Rev-Erbα knock-out mice revealed an increase in pulmonary neutrophilia and inflammation upon aerosolised LPS challenge. Moreover, by selectively deleting the REV-ERBα DNA binding domain (DBD) in the mouse bronchial epithelium, I observed exaggerated inflammatory responses to LPS and augmented CXCL5 secretion. Interestingly, a dual deletion of REV-ERBα DBD and REV-ERBβ in mouse bronchial epithelium had a more dramatic effect on neutrophil recruitment and chemokine secretion than deletion of just the REV-ERBα DBD; in both basal and bacterial challenged conditions. Ex-vivo analysis revealed bronchial epithelial cells and macrophages both responded to novel REV-ERBα synthetic ligand GSK1362 but displayed divergent inflammatory responses in presence of this compound. Finally, I observed a striking loss of REV-ERBα protein upon pro-inflammatory challenge. Further analysis revealed this degradation was dependent on the 26S proteasome and driven by sumoylation and ubiquitination of REV-ERBα. However, by using novel REV-ERB ligand GSK1362, these post-translational modifications were blocked and the protein protected from degradation. Collectively, my results propose a new model for a central role for REV-ERBα in conferring clock control to lung neutrophilic inflammation. I have also identified a feed-forward circuit activated by inflammatory stimuli, leading to suppression of the endogenous anti-inflammatory REV-ERBα protein. Finally, I have discovered a novel mechanism for small-molecule regulation of REV-ERBα, operating via suppression of endogenous protein ubiquitination process. These observations implicate REV-ERBα as a novel therapeutic target in human inflammatory disease.
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Jonasson, Sofia. "Lung mechanics and airway inflammation in murine models of asthma." Doctoral thesis, Uppsala universitet, Klinisk fysiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107061.
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Allergic asthma is an inflammatory disease of the airways and is characterized by eosinophilic inflammation and increased airway reactivity. In the studies presented in this thesis, lung mechanics and measurements of airway reactivity were assessed in anaesthetized tracheostomized mice by using an animal ventilator (flexiVent®). A forced oscillation technique makes it possible to measure of both airway and tissue mechanics with a potential to distinguish between central and peripheral airways. The results of the experiments on lung mechanics imply that it is important to understand how altered lung mechanics can affect the airway physiology in order to assess the relevance of different animal models of asthma. We have investigated the effects of changing different components of the lung mechanical measurements, such as administering bronchoconstrictive agents via inhalation or intravenously and implementing deep inhalation in animals with airway inflammation. We have also investigated the relation between airway inflammation and oxidative stress. We found that the formation and time-course of F2-isoprostanes, a marker of oxidative stress, and tissue damage were associated with the degree of inflammation and with the degree of heterogeneous airway airflow. Finally we wished to investigate the hypothesis that nitric oxide (NO) may interact with glucocorticoid (GC) treatment because we see a potential for finding new strategies to increase the therapeutic effect in poor responders or patients resistant to GC treatment. NO plays a central role in physiological regulation of the airway function, and is involved in asthma. We found that the concomitant administration of NO and GC attenuated the airway reactivity more than either treatment alone. In conclusion, with the information presented in this thesis, we hope to contribute to the development of better experimental tools and to improved understanding of murine models of asthma for investigating and understanding the underlying pathophysiology of asthma.
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Dakin, Carolyn Women's & Children's Health Faculty of Medicine UNSW. "Infection and inflammation in children with cystic fibrosis lung disease." Awarded by:University of New South Wales. Women's & Children's Health, 2009. http://handle.unsw.edu.au/1959.4/44624.
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The purpose of this study was to examine the relationships between inflammation, infection and lung function in cystic fibrosis during the evolution of lung disease in childhood and early adolescence. The developmental stages of childhood and the progression of lung disease together affected the methods and techniques used in the study, with the consequence that the work for this thesis fell naturally into two parts. The first part concerned the study of early lung disease in infants and young children who were unable to expectorate or to cooperate with lung function testing. In the second part, the inflammatory processes in both stable lung disease and during clinical exacerbations in older children and adolescents were studied non-invasively using sputum. The absence of a recognised definition of pulmonary exacerbation lead to further investigation into clinical heterogeneity in the diagnosis and management of an exacerbation. In early lung disease, inflammation was not found to be independent of infection, with pathogens in the lower airways found to correlate with levels of inflammation, respiratory system compliance and degree of air trapping (a relationship not previously shown). This suggested that infection remains the key target to minimizing lung damage in cystic fibrosis. The relationship between sputum markers of inflammation and lung pathology in established disease was found to be less clear, with high inflammation levels in both stability and during exacerbation. Reduction in sputum inflammatory levels following treatment of an exacerbation was found to be greater in those with lower pre-treatment levels. The definition and management of an exacerbation was found to be an area lacking consensus among clinicians, with likely consequent heterogeneity of clinical care and therefore inhomogeneity of hospitalization as a surrogate measure of exacerbation in a research setting. The work from this thesis, and the ensuing publications, has contributed to the understanding of the interactions between the inflammatory and infectious processes involved in CF lungdisease, in both early and more established lung disease in childhood.
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Yang, Fu. "Role and regulation of 11β-hydroxysteroid dehydrogenase in lung inflammation". Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4828.
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Glucocorticoids are steroid hormones that have potent anti-inflammatory actions. Endogenous glucocorticoid action is modulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyses the interconversion of active glucocorticoids (cortisol, corticosterone) and intrinsically inert forms (cortisone, 11-dehydrocorticosterone). There are 2 isozymes; 11β-HSD type 1 regenerates active glucocorticoids in vivo whereas 11β-HSD type 2 inactivates glucocorticoids. Although 11β-HSD1 is highly expressed in the lung, its role there has been little explored. In this study, the expression and localization of 11β-HSD1 mRNA in lung was confirmed by in situ hybridization. Immunohistochemical staining of mouse lung localized 11β-HSD1 to the cytoplasm of fusiform cells in alveolar walls, in a multivesicular pattern characteristic of interstitial fibroblasts. A lung fibrosis model of inflammation was used to test the role and regulation of 11β-HSD1. The results suggest that levels of 11β-HSD1 mRNA and enzyme were not changed during bleomycin-induced lung inflammation. However, 11β-HSD1-deficient mice showed a more severe inflammatory response than congenic wild-type controls, with greater inflammatory cell infiltration into the lung, and increased levels of HO-1 and iNOS mRNA 14 days following bleomycin installation into lung. Picrosirius red staining of lung sections suggested more collagen deposition in 11β-HSD1-deficient mice than in wild-type controls during the course of the lung inflammatory response. Moreover, whereas naïve 11β-HSD1-deficient mice had significantly lower collagen content in lung (84% of WT levels, p<0.05). 28d after bleomycin there was no significant difference between genotypes (KO having 94% of WT levels, p=0.42) confirming more collagen production in 11β-HSD1-deficient mice following bleomycin. Fibroblasts are critical in the regulation of inflammatory responses and are essential in the model of bleomycin-induced lung injury. Lung fibroblasts may have a different transcriptional regulation of 11β-HSD1 compared to other tissues. In the majority of tissues, 11β-HSD1 can be transcribed from 2 promoters; the P1 promoter is the main promoter used in lung, with other tissues mainly using the P2 promoter. To address the relevance of the P1 promoter in lung and to identify the cell type using the P1 promoter, mouse lungs were collagenase-digested to isolate primary fibroblast and epithelial cells. Isolated lung fibroblasts highly expressed 11β-HSD1, predominantly from the P1 promoter. During passage, primary lung fibroblasts switched promoter usage from P1 to P2. In fibroblast primary culture, treatment with TGF-β for 72h markedly decreased 11β-HSD1 expression to 38% of untreated levels, an effect which was reversed by SB431542, a TGF-β receptor antagonist. Whilst TGF-β reduced levels of mRNA initiating at the P2 promoter, initiation from the P1 promoter was completely repressed. Treatment with TGF-β receptor antagonist increased levels of P1-initiated 11β-HSD1 mRNA by 6.6-fold compared to untreated cells. These data suggest that the switch in 11β-HSD1 promoter usage may be regulated by TGF-β during an inflammatory response. Furthermore, as the P1 and P2 promoters are differentially regulated (e.g. by C/EBPβ, a cytokine-responsive transcription factor), the promoter switch may place 11β-HSD1 under a different transcriptional regulation during inflammation. Taken together, these results suggest that 11β-HSD1 deficiency worsens lung inflammation and results in greater lung fibrosis. Therefore, amplification of intracellular glucocorticoids levels, by 11β-HSD1, may represent an important mechanism to limit the inflammatory response and shape fibroblast function, limiting subsequent collagen production and fibrosis.
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Koch, Andrea. "Clinical Aspects of Inflammation in Non-small Cell Lung Cancer." Doctoral thesis, Linköpings universitet, Internmedicin, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-68749.
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Lung cancer is the most common cause of cancer death worldwide, with about 1.2 million deaths every year. In Sweden, about 3500 new cases are diagnosed every year. The majority of patients presents with advanced non-small cell lung cancer (NSCLC) and is treated with palliative intent. Standard treatment in these patients in performance status 0-2 is combination chemotherapy. Radiotherapy may be added for palliative purposes. Median survival time with such treatment is 6-10 months. New treatment strategies are urgently needed. There is growing evidence for a link between cancer and inflammation and consequently, inflammation may be a possible target for the treatment of lung cancer. The aim of this thesis was to study clinical aspects of inflammation in non-small cell lung cancer. A central issue was to adapt the projects as close to clinical routine as possible. In a retrospective study of 289 patients (paper I), we investigated the prognostic value of Creactive protein (CRP), a nonspecific marker of systemic inflammation, and smoking in patients with advanced NSCLC treated with palliative first-line chemotherapy. We found that patients with elevated CRP values (≥10 mg/ml) and current smokers at onset of treatment had inferior survival compared to patients with normal CRP values and patients who were not smoking. CRP and smoking status were independent prognostic factors and provided additional information to established prognostic factors such as stage of disease and performance status. The expression of COX-2, an important enzyme involved in inflammation, was prospectively analysed in 53 patients with cytologically diagnosed lung cancer (paper II). The study showed that the analysis of COX-2 expression in cytological material is technically easy to perform with routine diagnostic methods and results in good quality slides. There was great variation in the proportion of COX-2 positive cells between the patients as well as in the intensity of staining between individual cells in many single cases. The major project (paper III) of this thesis was the CYCLUS study, an academic, randomised, double-blind, phase III trial. The scientific question was if addition of the COX-2 inhibitor celecoxib to first-line palliative chemotherapy would prolong survival in patients with advanced NSCLC. 316 patients were included at 13 centres in Sweden. There was no survival difference between the treatment arms. Celecoxib appeared to have more favourable effect on survival in women than in men, but the differences were not significant. Small but not statistically significant differences in global quality of life and pain were seen favouring the celecoxib group. No increased incidence of cardiovascular events was observed in the celecoxib group.
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Brown, Sarah. "Mechanisms of resolution of inflammation in paediatric neutrophilic lung disease." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/56921.
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Many paediatric airway diseases are characterised by persistent neutrophilic inflammation, which can lead to damage to the airways and lung parenchyma. One possible mechanism for the persistence of neutrophilic inflammation is failure of the normal active resolution of the inflammatory process. There is limited published literature on the role of inflammatory resolution in paediatric inflammatory lung disease. It is possible that targeting inflammatory resolution mechanisms and the ability to “switch off” inflammation may provide therapeutic targets in the future for these diseases. This thesis investigates the hypotheses that failure of mechanisms terminating acute inflammation are important in the pathophysiology of infective and inflammatory lung disease; and that the differences in prognosis between childhood inflammatory lung diseases: cystic fibrosis (CF) (both established and newly diagnosed by newborn screening (CF NBS)), bronchiectasis, primary ciliary dyskinesia (PCD) and persistent bacterial bronchitis (PBB), are related to the ability to resolve inflammation in each disease. A number of mechanisms and mediators important for inflammatory resolution are described in a cross-sectional study of bronchoalveolar lavage (BAL) and endobronchial biopsies (EBB): BAL CD25+FoxP3+ T regulatory cells by flow cytometry; annexin A1 (AnxA1) and its receptor ALX by RT-PCR of BAL and RTPCR and immunofluorescent staining of EBB; the transcription factor Lung Krüppel- Like Factor by immunofluorescent staining of EBB; BAL lipid mediators by liquid chromatography – mass spectrometry and the lipid enzyme 15-lipoxygenase by immunofluorescent staining of EBB. Findings were related to underlying diagnosis, clinical status and airway inflammatory status (BAL neutrophils, CXCL8 and IL-10). The main abnormality found was in the AnxA1 axis, where BAL AnxA1 mRNA levels were lower in neutrophilic lung disease as compared to controls. However this was related to disease severity rather than the CFTR defect. The ratio of BAL CXCL8: IL- 10 was higher in CF as compared to other neutrophilic lung diseases and thus there was evidence that the ability of IL-10 to resolve CXCL8 mediated inflammation was reduced in CF. Therefore there was some evidence for the importance of inflammatory resolution mechanisms studied in the paediatric neutrophilic airway, and limited evidence to suggest that the anti-inflammatory function of IL-10 is impaired in CF.
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Barr, Laura Caroline. "Peripheral blood mononuclear cell depletion for experimental human lung inflammation." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/23705.
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Acute lung injury (ALI) affects a significant proportion of patients requiring critical care and is associated with high morbidity and mortality. Treatment is currently only supportive, with no pharmacological treatment yet shown to definitively improve outcome. There is evidence from murine models of ALI that monocytes play a key role in the development of the neutrophilic lung infiltration characteristic of ALI. Depletion of blood monocytes in mice given intra-tracheal lipopolysaccharide (LPS) significantly reduces pulmonary neutrophil influx, systemic neutrophilia and other markers of lung injury. In humans, monocyte-like cells have been documented in the bronchoalveolar lavage (BAL) fluid of patients with a variety of inflammatory lung conditions, including ALI. This thesis describes novel work performed in healthy human subjects to test whether, in an experimental model of human lung inflammation, depletion of circulating blood monocytes can ameliorate systemic and pulmonary inflammation. LPS inhalation is an established method of modelling ALI in healthy human subjects as it safely and consistently induces mild and self-limiting systemic and pulmonary inflammation. A preliminary study in a group of 12 healthy subjects confirmed the safety and efficacy of LPS inhalation compared to saline placebo. LPS inhalation induced a marked blood neutrophilia together with a rise in body temperature and heart rate and elevated BAL neutrophil and pro-inflammatory cytokine concentrations. This study also used flow cytometry to confirm the presence of pulmonary monocyte-like cells (PMLCs) in BAL fluid, which, although distinct from blood monocytes, could be clearly divided into two separate sub-types according to CD14/CD16 expression. LPS inhalation caused a rise in the number of circulating classical monocytes in blood and an expansion in the CD14++CD16- 'inducible' iPMLC subtype (reminiscent of classical blood monocytes), compared to the CD14++CD16+ 'resident' rPMLC subtype. This may represent transmigration of classical monocytes from blood across the pulmonary endothelium. In humans, mononuclear cell (MNC) leukapheresis provides a readily available method of depleting circulating blood monocytes. A second preliminary study, performed in a separate group of 6 healthy subjects, demonstrated that leukapheresis of four total blood volumes could be safely employed to deplete large numbers of circulating blood monocytes. Active recruitment of monocytes into circulating blood during leukapheresis did, however, limit the reduction in total circulating blood monocyte counts. This study also investigated, for the first time, the potential pulmonary effects of leukapheresis. Despite a relative prominence of iPMLCs in BAL fluid after leukapheresis, there was no evidence of significant neutrophil influx or a clinically important pro-inflammatory effect in the alveolar space. A randomised, double blind, placebo-controlled trial was then performed in a third group of 30 healthy human subjects who all inhaled LPS at baseline. There was no evidence that MNC leukapheresis (depletion group, n=15), compared to a sham procedure (sham group, n=15), attenuated the systemic and pulmonary inflammation induced by LPS inhalation, as measured by: blood neutrophil and plasma C-reactive protein (CRP) levels; by the neutrophil, protein and pro-inflammatory cytokine content of BAL fluid; and by [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET)-derived measures of global lung inflammation. MNC leukapheresis temporarily prevented the LPS-induced rise in circulating classical monocytes and was also associated with a small reduction in the estimated numbers of MNCs in BAL fluid. It did not, however, appear to affect the LPS-induced expansion in the iPMLC subtype. Further characterisation of the PMLC subtypes by flow cytometry/sorting and cell culture demonstrated that the iPMLC subtype was more pro-inflammatory but less mature and with a lower proliferation potential than the rPMLC subtype. In summary, this work did not support a role for circulating blood monocytes in the evolution of LPS-induced systemic or pulmonary neutrophilia in man. The rise in circulating levels of classical blood monocytes and the dramatic expansion of pro-inflammatory, immature iPMLCs in BAL fluid after LPS inhalation do, however, suggest that monocytes migrate to the lung and are to some extent involved in the pathogenesis of lung inflammation. Compared to murine methods of monocyte depletion, leukapheresis could not achieve such an extensive or sustained reduction in circulating blood monocyte counts, nor was it likely to have influenced other (specifically patrolling or splenic) monocyte pools. Future work in the drive to find treatments for ALI should therefore investigate the potential of pre-emptive leukapheresis or the efficacy and safety of other methods of human monocyte depletion in experimental lung inflammation.
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MacGregor, Gordon. "Non-invasive markers of inflammation in cystic fibrosis lung disease." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4834.
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Cystic fibrosis (CF) lung disease is characterised by early airways infection and inflammation, chronic suppuration, frequent infective exacerbations and an increased influx of acute, and chronic inflammatory cells. The inflammatory process involves activation of many cell types including neutrophils, macrophages and epithelial cells, and leads ultimately to the development of progressive respiratory failure and death. Accurate assessment of the inflammatory process is a crucial part of disease monitoring and should allow appropriate evaluation of therapeutic interventions so as to maximize control of the respiratory sequelae of the disorder. Lung function markers such as FEV1 are insensitive and indirect. Direct but invasive methods such as fibreoptic bronchoscopy and biopsy are limited in application, repeatability and safety. Non-invasive methods of assessment are, therefore, attractive. Exhaled Breath Gases, Exhaled Breath Condensate and Induced Sputum provide potential for such measures. These techniques are safe, simple, repeatable and could assess all airways and can be used in children as young as 6 years. We hypothesised that biomarkers of inflammation in Cystic Fibrosis Lung Disease are measurable in samples collected noninvasively, and can be developed into clinically useful assays. These assays would have the ability to reflect the level of inflammation in the CF lungs as well as holding the potential to act as surrogate markers of CFTR function. Methods Non-invasive markers of inflammation in Cystic Fibrosis lung disease Methods. Exhaled breath gases, exhaled breath condensate, bronchoalveolar lavage fluid and induced sputum were investigated using a number of analysis techniques to identify the markers which best discriminated CF from non CF subjects. Analysis techniques used were electrochemical cells, chemiluminescene, ELISA, EIA, ion selective probes and mass spectrometry. Results Markers found to discriminate CF from non CF subjects were EBC pH and ammonium, and 38 proteomic markers were found in induced sputum. 21 proteomic markers were found in bronchoalveolar lavage fluid. One biomarker has been identified with confidence, Calgranulin A. Discussion A large component of the work of this thesis was focussed on exhaled breath condensate. Two markers, pH and Ammonium were different between the CF and control groups. The measurement of EBC pH and ammonium as markers of inflammation should be used in future gene therapy trials as they are cheap, quick and simple to perform Using clean techniques free from contamination, no proteins are repeatedly detectable in EBC using highly sensitive SELDI techniques. This technique reflects the highest sensitivity of any available proteomics instrument and therefore until new technologies become available, it would be incorrect to assay any proteins in EBC. The induced sputum proteomics study identified 38 independent markers of CF lung inflammation Therefore, sampling by collection of induced sputum should be used in gene therapy trials. The endpoints should be assessed by a combination of SELDI as an endpoint and by ELISA where this is available. The marker Calgranulin is likely to report on neutrophil recruitment to the lung. It is anticipated that this will be a sensitive marker of inflammation in the lung and it also has the potential to report on successful of gene transfer as it is raised in heterozygote carriers as well as homozygotes with CF. Therefore, the non-invasive technique induced sputum coupled to proteomic analysis would have the ability to reflect the level of inflammation in CF subjects and may also report on CFTR function.
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Singh, Ravinder. "The role of Death Receptor 3 in allergic lung inflammation." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/56963/.
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Death Receptor 3 (DR3) is a death domain containing member of the TNF Receptor Superfamily (TNFRSF), refereeing a range of cellular responses from differentiation and proliferation to cell death, depending upon the context of receptor activation. DR3 has been reported to have a role in many inflammatory diseases, including inflammatory arthritis and inflammatory bowel disease. The aim of this study was to determine the contribution of DR3 in a mouse model of acute and chronic allergic lung inflammation. Mice genetically deficient in the DR3 gene (DR3ko) were resistant to cellular accumulation within the lungs and bronchoalveolar lavage following acute lung inflammation, induced by priming with ovalbumin (OVA) and the adjuvant aluminium hydroxide (Alum) prior to 2 OVA aerosol exposures. To discern the role of DR3 in a more physiologically relevant chronic model of allergic lung inflammation, mice underwent repeated inhalation challenges with OVA subsequent to priming with OVA and Alum. Whilst cellular accumulation did not differ, DR3ko mice displayed reduced immuno-histopathology, and goblet cell hyperplasia, hallmarks of the asthmatic phenotype. Intriguingly, DR3ko mice exhibited reduced accumulation of various cell types into the spleen in both models. Early priming events were therefore investigated, prior to aerosolised antigenic challenge to decipher the effects of DR3. One sensitisation injection was sufficient to induce decreased DR3ko splenocyte accumulation, though T and B cell responses were observed to be comparable between DR3ko and DR3wt controls. DR3ko mice had depleted CXCL10 levels, suggesting cellular recruitment in response to inflammation is DR3 dependent. The underlying DR3 dependent mechanisms concerning the DR3ko splenic defects are under further investigation and may have impact on the use of the DR3/TL1A pathway as a therapeutic target, either as an anti-inflammatory or as a booster of the immune response to pathogens.
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Xin, Gang. "The role of TREM proteins in lung homeostasis and inflammation." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/9058.
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The family of Triggering Receptors Expressed on Myeloid Cells (TREM) contain novel activating receptors of the Ig super-family that are expressed on myeloid cells. TREM-1 is a transmembrane glycoprotein expressed on blood neutrophils and a subset of monocytes, but not on lymphocytes or other cell types and is upregulated by bacterial and fungal products. TREM-1 signaling potentiates the outcome of Toll-like Receptor (TLR) signaling. Blockade of TREM-1 prevents experimentally induced septic shock. In addition to the membrane-bound form, a soluble TREM-1 molecule (sTREM-1) exists that regulates membrane bound TREM-1 by competing against the, as yet, unknown natural TREM-1 ligand. sTREM-1 is detected at high levels during bacterial infection and asthma and is used as a predictive biomarker for severe inflammation. TREM-2 on, the other hand is not known to be secreted and the membrane bound form is reported to prevent TLR signaling and promote osteoclastogenesis. The expression and function of TREM proteins during respiratory viral infection is not currently known. In this thesis we investigate the hypothesis that TREM-1 signaling contributes to excessive cytokine production during pulmonary viral infection in a murine model and that soluble TREM-1 and membrane bound TREM-2 proteins are anti-inflammatory. We show, for the first time, the following novel mechanisms that significantly increase our understanding of this important receptor family: 1) TREM-1 is highly up-regulated during influenza and the subsequent release of sTREM-1 likely contributes to secondary bacterial super-infection, 2) Blockade of TREM-1 at the onset of viral infection significantly reduces the risk of secondary bacterial pneumonia and 3) TREM-2 expressing macrophages that appear during the resolution of influenza-induced inflammation display a regulatory phenotype that can reduce TLR responsiveness of inflammatory macrophages. Taken together, our data suggests that TREM-1 proteins represent a novel therapeutic target for the alleviation of influenza-induced pathology and that TREM-2 expression identifies a novel population of regulatory macrophages.
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White, Anna-Marie. "The role of tumour necrosis factor α in lung inflammation". Thesis, University of Bath, 1996. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362198.
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Morla, Shravan. "Glycosaminoglycan Mimetics for the Treatment of Cancer and Lung Inflammation." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5948.
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Glycosaminoglycans (GAGs) are linear polysaccharides whose disaccharide building blocks consist of an amino sugar and either uronic acid or galactose. They are expressed on virtually all mammalian cells, usually covalently attached to proteins, forming proteoglycans. GAGs are highly negatively charged due to an abundance of sulfate and carboxylic acid groups, and are structurally very diverse, with differences arising from chain length, the type of monomeric units, the linkages between each monomeric unit, the position of sulfate groups, and the degree of sulfation. GAGs are known to interact with a multitude of proteins, impacting diverse physiological and pathological processes. In addition, most of the biological interactions mediated by proteoglycans are believed to be primarily because of the GAG chains present on their surface. Considering the involvement of GAGs in multiple diseases, their use in the development of drugs has been of significant interest in the pharmaceutical field. Heparin, the first GAG-based drug developed in 1935, is still the most widely used anticoagulant in the world. The therapeutic potential of GAGs for the treatment of many other disease states, including cancer, inflammation, infection, wound healing, lung diseases, and Alzheimer’s disease, is being actively studied with many GAGs currently in clinical trials. However, challenges associated with the heterogeneous and complex structure of GAGs, limit their successful development. To combat such issues, our lab has focused on developing Non- Saccharide GAG Mimetics (NSGMs) as structural mimics of GAGs. NSGMs, being synthetic molecules, offer multiple advantages over GAGs. The studies mentioned here describe our efforts in the development of NSGMs as potential therapeutics for cancer, and cystic fibrosis.
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McNeil, Kathryn Suzanne. "Nitrosative and oxidative stress in Nippostrongylus brasiliensis induced pulmonary inflammation." Thesis, Edinburgh Napier University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312974.
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Hedbrant, Alexander. "Cancer and Inflammation : Role of Macrophages and Monocytes." Doctoral thesis, Karlstads universitet, Institutionen för hälsovetenskaper, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-37086.
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Macrophages are cells of the innate immune system that can be found in large quantities in cancer tumors and affect cancer progression by regulating growth and invasiveness of cancer cells. There are two main phenotypes of macrophages denoted M1 and M2. In this thesis, the M1 and M2 phenotype of human macrophages were characterized, and effects of the macrophages on the growth and invasiveness of colon and lung cancer cells were studied. Macrophages of the M1 phenotype, but not the M2 phenotype, inhibited growth of both colon and lung cancer cells, and the inhibition for some of the cancer cell lines was induced by cell cycle arrest in the G1/G0 and/or G2/M cell cycle phases. In the colon cancer cell line, the macrophage induced cell cycle arrest was found to attenuate the cytotoxic effect of the chemotherapeutic drug 5-FU. Macrophages were also shown to express high levels of proteases (matrix metalloproteinase-2 and 9) and high levels of proteins of the urokinase-type plasminogen activator (uPA) system, in comparison to the lung cancer cell lines studied. Expression of these has been found to predict poor outcome in lung cancer, and the results suggest macrophages to be important contributors of these in lung tumors. Furthermore, the M1 phenotype was found to express higher levels of the uPA receptor than the M2 phenotype. Prostaglandin E2 (PGE2) is a potent inflammatory molecule expressed by e.g. macrophages and monocytes, and inhibition of its expression has been shown to reduce the risk of colon cancer. Green tea and black tea was found to be potent inhibitors of PGE2 formation in human monocytes, and the inhibitory effects of green tea was likely due to its content of the polyphenol epigallocatechin gallate. Rooibos tea also inhibited PGE2 formation, but was less potent than green and black tea. The primary mechanism for the inhibition was via inhibition of expression of enzymes in the PGE2 formation pathway, and primarily microsomal prostaglandin synthase-1.<br>Macrophages are cells of the immune system often found in large numbers in cancer tumors. They affect multiple aspects of cancer progression, including growth and spread of cancer cells, and the efficacy of treatments. There are two major macrophage phenotypes denoted M1 and M2, that have mainly pro- and anti-inflammatory properties, respectively. In this thesis, M1 and M2 macrophages were characterized and effects of them on different aspects of cancer progression were studied using culture of colon, and lung cancer cells. The M1 phenotype inhibited proliferation of cancer cells from both colon and lung. The growth inhibition was for some cell lines accompanied by cell cycle arrest. The macrophage induced cell cycle arrest was found to protect colon cancer cells from the cytostatic drug 5-fluorouracil. Prostaglandin E2 (PGE2) contributes to colon cancer development and treatment of monocytes with tea extracts inhibited PGE2 formation via inhibition of expression of microsomal prostaglandin E synthase-1. Proteases can degrade the extracellular matrix of a tumor to facilitate cancer cell invasion and metastasis. The M1 and M2 phenotypes of macrophages expressed several protease activity related genes to a greater extent than lung cancer cells, and M1 more so than the M2 phenotype.
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Sánchez, Vidaurre Sara. "Non-invasive methods to study lung inflammation in work-related asthma." Doctoral thesis, Universitat Autònoma de Barcelona, 2012. http://hdl.handle.net/10803/96716.
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El asma relacionado con el trabajo (ART) incluye el asma ocupacional (AO) y el asma exacerbado por el trabajo (AET), y representa un problema de salud importante con un negativo impacto socio-económico. El AO se refiere al asma causado de novo por exposición a un agente específico en el lugar de trabajo, y el AET se define como un empeoramiento de un asma preexistente o concomitante agravado por las condiciones de trabajo.
Al igual que el asma bronquial, el ART es una enfermedad inflamatoria crónica heterogénea de las vías respiratorias. La inflamación bronquial es un reflejo directo de la enfermedad y su evaluación de forma no invasiva presenta un interés creciente para comprender los mecanismos fisiopatológicos implicados en las enfermedades inflamatorias respiratorias El objetivo de esta tesis fue establecer la utilidad de dos métodos no invasivos: esputo inducido (EI) y condensado de aire exhalado (CAE), en la evaluación de la inflamación en pacientes con sospecha de ART.
Inicialmente se realizaron dos estudios, en pacientes asmáticos con asma estable y en una población adulta sana, para proporcionar datos de referencia para los respectivos estudios realizados posteriormente con muestras de EI y de CAE en sujetos con sospecha de ART. En pacientes controles con asma estable, se observó que la inflamación y la hiperrespuesta bronquial persisten en la mayoría de éstos a pesar del tratamiento, y que cuando la hiperrespuesta persiste, ésta es más grave en pacientes con una inflamación eosinofílica. El segundo estudio se realizó en adultos sanos estratificados según edad, y se observó que los valores de pH y los niveles de 8-isoprostano en el CAE presentaron relación con la edad, sugiriendo que los valores obtenidos en estudios con grupos controles deberían ser ajustados por este factor.
La evaluación de la inflamación bronquial en el ART permitió mejorar nuestros conocimientos sobre los mecanismos fisiopatológicos implicados en los diferentes tipos de ART. Al realizar estudios de inflamación bronquial es necesario distinguir entre los diferentes tipos de agentes ocupacionales: de alto peso molecular (APM) y de bajo peso molecular (BPM). Se investigó el perfil inflamatorio de sujetos con sospecha de ART mediante contajes celulares diferenciales y biomarcadores inflamatorios en muestras de EI antes y después de una prueba de provocación bronquial específica (PPBE). Se encontró un incremento de eosinófilos y neutrófilos y de interleuquina (IL) -10, y una disminución de leucotrieno B4 (LTB4) en EI tras la exposición a agentes de APM. Estos resultados refuerzan la teoría de que la mayoría de los agentes de APM inducen AO a través de un mecanismo mediado por IgE, dando lugar a una respuesta alérgica tipo Th2. No se observaron diferencias significativas en los recuentos celulares diferenciales ni en los niveles de biomarcadores inflamatorios en muestras de EI de pacientes expuestos a agentes de BPM. Sin embargo, se observó que la exposición a agentes de BPM puede ocasionar un aumento de la inflamación neutrofílica en pacientes con enfermedades respiratorias previas, sugiriendo la existencia de diferentes mecanismos de acción en función de si el agente de BPM causa AO o bien provoca empeoramiento de una enfermedad respiratoria preexistente.
Al investigar el perfil inflamatorio de sujetos con sospecha de ART mediante el análisis del CAE, se observó que tras la exposición al agente causal el pH del CAE mostró una sensibilidad del 79% y una especificidad del 100% para el diagnóstico del AET, lo que demuestra que este biomarcador conjuntamente con la PPBE puede ser útil para el diagnóstico del AET, y sugiere de nuevo que el mecanismo de acción de los agentes de BPM parece variar en función de si éstos causan AO o inducen AET.<br>Asthma is a chronic disorder of the airways characterized by reversible airway obstruction, airway inflammation and non-specific airway hyper-reactivity (AHR). Up to 25% of all asthma cases developing in adulthood are caused by occupational exposure. This condition is known as work-related asthma (WRA); it includes both occupational asthma (OA) and work-exacerbated asthma (WEA), and it presents a major health challenge with adverse socio-economic impact. OA refers to de novo asthma caused by exposure to an agent specific to a workplace, and WEA is defined as a worsening of pre-existing or concomitant asthma which is exacerbated by working conditions.
Like bronchial asthma, WRA is a heterogeneous chronic inflammatory disorder of the airways. Airway inflammation is a direct reflection of the disease and its assessment in a non-invasive manner does not disturb the underlying disease process and allows its monitoring. Recently, this practice has aroused growing interest in the attempts to understand the pathophysiological mechanisms of inflammatory airway diseases. This thesis aimed to establish the usefulness of two non-invasive methods: induced sputum (IS) and exhaled breath condensate (EBC) for the assessment of airway inflammation in subjects with suspected WRA.
Two studies were carried out in asthmatic patients with ell-controlled asthma and in a healthy adult sample as control groups in order to provide reference data for the respective studies performed later with IS and EBC samples in subjects with suspected WRA. Evaluating the type and degree of airway inflammation present in these control patients with well-controlled asthma we found that airway inflammation and AHR persist in most patients despite of treatment and that when AHR persists, it is more severe in patients with eosinophilic inflammation. The second study was carried out in healthy adults stratified into groups according to age, in order to establish reference values for certain biomarkers of airway inflammation and to determine whether there are age-associated differences. pH values and 8-isoprostane levels in EBC showed a relationship with age, suggesting that the values obtained in studies with control groups should be adjusted for this factor.
Assessment of airway inflammation in WRA improved our understanding of the pathophysiological mechanisms implicated in the genesis of the different types of WRA. In this context, it seems necessary to distinguish between the different types of occupational agents: high-molecular-weight (HMW) and low-molecular-weight (LMW), when conducting airway inflammation studies. We investigated the inflammatory profile by evaluating sputum differential cell counts and several inflammatory biomarkers in sputum supernatants of subjects with suspected WRA preceding and following a specific inhalation challenge (SIC). Increases in sputum eosinophils and neutrophils and in interleukin (IL)-10 concentration and a decrease in leukotriene B4 (LTB4) after exposure to HMW agents have been reported. These findings support the notion that most HMW agents induce OA via an IgE-mediated mechanism inducing a Th2-mediated allergic response. No significant changes in sputum differential cell counts or inflammatory biomarkers were found after SIC in patients with OA due to exposure to LMW agents. However, exposure to LMW agents can result in increased neutrophilic inflammation in patients with airway diseases unrelated to OA, suggesting different mechanisms of action according to whether the LMW agent is the cause of OA or provokes aggravation of a pre-existing respiratory disease.
Investigating the inflammatory profile by analysing EBC in subjects with suspected WRA, EBC pH after exposure to the offending agent had a sensitivity of 79% and specificity of 100% for the diagnosis of WEA, demonstrating that in conjunction with SIC this biomarker may be useful for diagnosing WEA, and suggesting again that the mechanism of action of LMW agents seems to differ according to whether they cause OA or induce WEA.
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Thakur, Sheetal A. "Role of scavenger receptor MARCO in particle uptake and lung inflammation." The University of Montana, 2009. http://etd.lib.umt.edu/theses/available/etd-10302008-102542/.
Full textAbstract:
Alveolar macrophages (AM) form the first line of defense against chronic inflammation caused by occupational exposure to environmental particulates such as crystalline silica (CSiO2). The chronic inflammatory process triggered by CSiO2 is known to culminate into a fibrotic response called silicosis in the human lungs. Previous studies have indicated the role of membrane glycoproteins called scavenger receptors in binding of environmental particles. The scavenger receptors are classified into different classes (A-H) based on their structure and function. Class A scavenger receptors are critical in uptake of variety of ligands such as bacteria, acetylated lipoproteins and are typically found on macrophages, dendritic and epithelial cells. One of the members of this family is Macrophage receptor with collagenous structure (MARCO). Recent studies have focused on analyzing the interaction between MARCO and inorganic particles such as CSiO2 and titanium dioxide (TiO2). Both in vivo and in vitro binding studies have identified MARCO as a key receptor in CSiO2 uptake and subsequent cytotoxicity in AM from C57Bl/6 mice. Further in vitro studies using a transfected cell line revealed that the 100 amino acid residues long cysteine-rich (SRCR) domain at the C-terminal end of MARCO is required for binding of inorganic particles such as CSiO2, TiO2 and amorphous silica (ASiO2). Moreover, individual particles bind to SRCR domain of MARCO with unique differences and have varying requirements with respect to need for divalent cations. Our studies demonstrate that physiological absence of MARCO in C57Bl/6 mice leads to a more robust inflammatory response following CSiO2 exposure as compared to wild-type mice. The results suggest that diminished clearance of CSiO2 particles from the MARCO-/- lungs exacerbates the lung inflammation. These findings demonstrate that the involvement of different regions of SRCR domain may distinguish downstream events following particle binding. Taken together, these data establish the role of MARCO in uptake of various inorganic particles and elucidate the protective role of MARCO in CSiO2-induced lung inflammation.
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Cornejo, Perales Salomon. "Mechanisms of glucocorticoid responsiveness in the lung during development and inflammation." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116918.
Full textAbstract:
Glucocorticoids (GCs) are vital hormones involved in lung development and the regulation of the inflammatory/immune response. High inter-individual variability in GC responsiveness exists among patients using steroids as treatment for inflammatory diseases. Evidence suggests that vitamin D (VitD), another player in lung development, improves GC function. Even though progress has been made in the study of steroid insensitivity, the molecular mechanisms are not completely elucidated and the effects of limited GC response during lung development have not been explored. The first objective of the present thesis was to study mechanisms of steroid responsiveness in asthma using mouse models of the disease. The Balb/c strain demonstrated a steroid insensitive phenotype associated with increased amounts of active p38 MAPK and subsequent inactivation of the GC receptor (GR) following allergen challenge. Additionally, lymphoblast cell lines derived from asthmatic children were used to study mechanisms for variable GC responsiveness and to explore the modulatory role of VitD on GC function. Poor responsiveness to steroids in asthmatic children was associated with limited GR nuclear bioavailability as a consequence of decreased baseline GR expression and faster hormone-induced downregulation. Suggestive evidence for a beneficial effect of VitD in steroid sensitivity is presented. Finally, steroid responsiveness and VitD modulation of GC function was studied in epithelial cells of the developing lung of normoresponsive and atopic rat models. The developmental airway epithelium of the atopic rat appeared to be more sensitive to steroids, possibly making the lung more susceptible to the deleterious effects of GCs, and VitD attenuated the GC response. Overall this thesis highlights the complexity of steroid function and its regulation by multiple mechanisms ranging from altered expression, reduced activation, abnormal nuclear translocation and increased homologous downregulation of GR.<br>Les glucocorticoïdes (GC) sont des hormones vitales impliquées dans le développement des poumons et de la régulation de la réponse inflammatoire/immunitaire. Une grande variation interindividuelle de la réactivité des GC existe chez les patients utilisant des stéroïdes comme traitement pour les maladies inflammatoires. Les preuves suggèrent que la vitamine D (VitD), une autre molécule impliquée dans le développement des poumons, améliore la fonction des GC. Même si des progrès ont été réalisés dans l'étude de l'insensibilité aux stéroïdes, les mécanismes moléculaires ne sont pas complètement élucidés et les effets de la réponse compromise aux GC au cours du développement pulmonaire n'ont pas été explorés. Le premier objectif de cette thèse est d'étudier les mécanismes de réactivité des stéroïdes dans l'asthme en utilisant des modèles murins de la maladie. La souche Balb/c a démontré un phénotype d'insensibilité aux stéroïdes associé à des quantités accrues de p38 MAPK sous forme active et l'inactivation subséquente du récepteur des GC (GR) après provocation par un allergène. De plus, des lignées cellulaires lymphoblastiques provenant d'enfants asthmatiques ont été utilisées pour étudier les mécanismes de réactivité variable des GC et ont permis d'explorer le rôle modulateur de la VitD sur la fonction des GC. Chez les enfants asthmatiques, une faible réactivité aux stéroïdes a été associée à une biodisponibilité nucléaire limitée du GR à la suite de l'expression basale diminuée du GR et de la rapide régulation négative induite par l'hormone. Des évidences suggérant un effet bénéfique de la VitD sur la sensibilité aux stéroïdes sont présentées. Enfin, la réactivité des stéroïdes et la modulation de la fonction des GC par la VitD ont été étudiées dans les cellules épithéliales du poumon en développement des modèles de rats normaux et atopiques. L'épithélium des voies respiratoires du rat atopique semble être plus sensible aux stéroïdes, en rendant possiblement les poumons plus susceptibles aux effets néfastes des GC, et la réponse des GC est atténuée par la VitD. Cette thèse met en évidence la complexité de la fonction de stéroïdes et de sa régulation par des mécanismes multiples allant de l'expression altérée, l'activation réduite, la translocation nucléaire anormale et l'augmentation de la régulation négative homologue des GC.