Добірка наукової літератури з теми "Lungs Inflammation"

The mechanisms of excessive migration of activated neutrophils into inflamed lungs, credited with tissue damage, are not fully understood. We explored the hitherto unknown expression of leukocyte-specific protein 1 (LSP1) in human and mouse lungs and neutrophils and examined its role in neutrophil migration in acute lung inflammation. Autopsied septic human lungs showed increased LSP1 labeling in epithelium, endothelium, and leukocytes, including in their nuclei compared with normal lungs. We induced acute lung inflammation through intranasal administration of E. coli lipopolysaccharide (LPS) (80 μg) in LSP1-deficient ( Lsp1−/−) and wild-type (WT) 129/SvJ mice. Immunocytochemistry and Western blots showed increased expression of LSP1 and phosphorylated LSP1 in lungs of LPS-treated WT mice. Histology showed more congestion, inflammation, and Gr-1+neutrophils in lung of WT mice than Lsp1−/−mice. LPS-treated WT mice had significantly more neutrophils in bronchoalveolar lavage (BAL) and myeloperoxidase levels in lungs compared with Lsp1−/−mice. However, there were no differences in lung tissue and BAL concentrations of keratinocyte-derived chemokine, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α and -1β, vascular permeability, and phosphorylated p38 MAPK between LPS-treated WT and Lsp1−/−mice, whereas TNF-α concentration was higher in BAL fluid from LPS-treated WT. Immunoelectron microscopy showed increased LSP1 in the nuclei of LPS-treated neutrophils. We also found increased levels of phosphorylated LSP1 associated with plasma membrane, nucleus, and cytosol at various times after LPS treatment of murine bone marrow-derived neutrophils, suggesting its role in modulation of neutrophil cytoskeleton and the membrane. These data collectively show increased expression of LSP1 in inflamed mouse and human lungs and its role in neutrophil recruitment and lung inflammation.

Pulmonary surfactant participates in the regulation of alveolar compliance and lung host defense. Surfactant homeostasis is regulated through a combination of synthesis, secretion, clearance, recycling, and degradation of surfactant components. The extracellular pool size of surfactant protein (SP) D fluctuates significantly during acute inflammation. We hypothesized that changes in SP-D levels are due, in part, to altered clearance of SP-D. Clearance pathways in rats were assessed with fluorescently labeled SP-D that was instilled into control lungs or lungs that had been treated with lipopolysaccharide (LPS) 16 h earlier. SP-D clearance from lavage into lung tissue was time dependent from 5 min to 1 h and 1.7-fold greater in LPS-treated lungs than in control lungs. Analysis of cells isolated by enzymatic digestion of lung tissue revealed differences in the SP-D-positive cell population between groups. LPS-treated lungs had 28.1-fold more SP-D-positive tissue-associated neutrophils and 193.6-fold greater SP-D association with those neutrophils compared with control lungs. These data suggest that clearance of SP-D into lung tissue is increased during inflammation and that tissue-associated neutrophils significantly contribute to this process.

Nerve growth factor (NGF) controls sensorineural development and responsiveness and modulates immunoinflammatory reactions. Respiratory syncytial virus (RSV) potentiates the proinflammatory effects of sensory nerves in rat airways by upregulating the substance P receptor, neurokinin 1 (NK1). We investigated whether the expression of NGF and its trkA and p75 receptors in the lungs is age dependent, whether it is upregulated during RSV infection, and whether it affects neurogenic inflammation. Pathogen-free rats were killed at 2 (weanling) to 12 (adult) wk of age; in addition, subgroups of rats were inoculated with RSV or virus-free medium. In pathogen-free rats, expression of NGF and its receptors in the lungs declined with age, but RSV doubled expression of NGF, trkA, and p75 in weanling and adult rats. Exogenous NGF upregulated NK1 receptor expression in the lungs. Anti-NGF antibody inhibited NK1 receptor upregulation and neurogenic inflammation in RSV-infected lungs. These data indicate that expression of NGF and its receptors in the lungs declines physiologically with age but is upregulated by RSV and is a major determinant of neurogenic inflammation.

We have created the experimental model of chronic inflammation of lungs by means of prolonged mechanical irritation of the bronchi in 30 outbred rats and studied the morphological changes in the lung tissue of these animals rats in three series of experiments. Each rat was given an intraperitoneal injection of an ozonised saline solution produced by a «Binafsha» ozonator. The objective of the study was to compare a control group of healthy animals and the group of experimental animals with chronic purulent pneumonia. The prolonged irritation of the respiratory tract in experimental animals was found to induce the structural changes in the tissues of the lungs characteristic of chronic purulent inflammation. The course of treatment with the ozonised saline solution in healthy animals with experimentally modelled chronic purulent inflammation of the lungs did not have a negative impact on the general condition and the behaviour of the animals. The treatment of experimental chronic inflammation of lungs caused by prolonged mechanical irritation of the respiratory tract resulted in the improvement of the morphological status of the laboratory animals, but the purulent inflammation process failed to be completely resolved after the treatment which needs to be taken into consideration in the clinical practice.

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.

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.
Ph. D.
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.

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.

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.

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.
published_or_final_version
Medicine
Doctoral
Doctor of Philosophy

This is a document explaining in detail my artistic practice from childhood to the day I graduated VCU. It will perhaps only be understood by those who have themselves already felt such ways, or similar ways – words and ghosts are mostly invisible.