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Jonathan, Steven, Triya Damayanti, and Budhi Antariksa. "Pathophysiology of Emphysema." Jurnal Respirologi Indonesia 39, no. 1 (January 2, 2019): 60–69. http://dx.doi.org/10.36497/jri.v39i1.43.
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Pulmonary emphysema is part of pathological condition in chronic obstructive pulmonary disease (COPD) which is characterized by lung parenchymal destruction. Morphology classification of emphysema had been made according to histologic structure in pathology. There were some causes known to be the culprit of emphysema; one that caught most attention is protease-antiprotease activity from cigarette smoke exposure. Destructive effect of emphysema gives disturbance of lung function in expiration (obstruction). The primary mechanism is elastic recoil reduction which causes air trapping, lung volume increase, lung compliance increase and airways that is susceptible to collapse. Hyperinflation in emphysema causes some disadvantages which complicate inspiration and give a dyspnea sensation. Equal pressure point drop in emphysema happens because of elastic recoil reduction. This drop may cause early airway closure. (J Respir Indo 2019; 39(1): 60-9)
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Amariei, Diana E., Neal Dodia, Janaki Deepak, Stella E. Hines, Jeffrey R. Galvin, Sergei P. Atamas, and Nevins W. Todd. "Combined Pulmonary Fibrosis and Emphysema: Pulmonary Function Testing and a Pathophysiology Perspective." Medicina 55, no. 9 (September 10, 2019): 580. http://dx.doi.org/10.3390/medicina55090580.
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Combined pulmonary fibrosis and emphysema (CPFE) has been increasingly recognized over the past 10–15 years as a clinical entity characterized by rather severe imaging and gas exchange abnormalities, but often only mild impairment in spirometric and lung volume indices. In this review, we explore the gas exchange and mechanical pathophysiologic abnormalities of pulmonary emphysema, pulmonary fibrosis, and combined emphysema and fibrosis with the goal of understanding how individual pathophysiologic observations in emphysema and fibrosis alone may impact clinical observations on pulmonary function testing (PFT) patterns in patients with CPFE. Lung elastance and lung compliance in patients with CPFE are likely intermediate between those of patients with emphysema and fibrosis alone, suggesting a counter-balancing effect of each individual process. The outcome of combined emphysema and fibrosis results in higher lung volumes overall on PFTs compared to patients with pulmonary fibrosis alone, and the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio in CPFE patients is generally preserved despite the presence of emphysema on chest computed tomography (CT) imaging. Conversely, there appears to be an additive deleterious effect on gas exchange properties of the lungs, reflecting a loss of normally functioning alveolar capillary units and effective surface area available for gas exchange, and manifested by a uniformly observed severe reduction in the diffusing capacity for carbon monoxide (DLCO). Despite normal or only mildly impaired spirometric and lung volume indices, patients with CPFE are often severely functionally impaired with an overall rather poor prognosis. As chest CT imaging continues to be a frequent imaging modality in patients with cardiopulmonary disease, we expect that patients with a combination of pulmonary emphysema and pulmonary fibrosis will continue to be observed. Understanding the pathophysiology of this combined process and the abnormalities that manifest on PFT testing will likely be helpful to clinicians involved with the care of patients with CPFE.
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Keller, Cesar A. "Pathophysiology and classification of emphysema." Chest Surgery Clinics of North America 13, no. 4 (November 2003): 589–613. http://dx.doi.org/10.1016/s1052-3359(03)00092-9.
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Gronbach, Judith, Harald Ehrhardt, Klaus-Peter Zimmer, and Markus Waitz. "Early Pulmonary Interstitial Emphysema in Preterm Neonates—Respiratory Management and Case Report in Nonventilated Very Low Birth Weight Twins." American Journal of Perinatology Reports 08, no. 02 (April 2018): e99-e105. http://dx.doi.org/10.1055/s-0038-1648253.
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AbstractEarly pulmonary interstitial emphysema in extreme preterm neonates is closely linked with respiratory distress syndrome and exposure to mechanical ventilation. In severe cases, maintaining adequate gas exchange aiming to avoid further lung damage and other neonatal morbidities associated with systemic/pulmonary hypoperfusion, prolonged hypoxia, and respiratory acidosis can be challenging and requires in-depth knowledge into the pathophysiology of the disease. Herein, we report on very low birth weight twins who developed early pulmonary interstitial emphysema during noninvasive respiratory support. We further review the current evidence from the literature, specifically addressing on possible preventive measures and the respiratory management options of this acute pulmonary disease in high-risk neonates.
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Portillo, Karina, and Josep Morera. "Combined Pulmonary Fibrosis and Emphysema Syndrome: A New Phenotype within the Spectrum of Smoking-Related Interstitial Lung Disease." Pulmonary Medicine 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/867870.
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Combined pulmonary fibrosis and emphysema (CPFE) is a recently defined syndrome, in which centrilobular and/or paraseptal emphysemas in upper lung zones coexist with pulmonary fibrosis in lower lobes in individuals. These patients have a characteristic lung function profile, with unexpected subnormal dynamic and static lung volumes, contrasting with a significant reduction of carbon monoxide transfer (DLco) and exercise hypoxemia. Pulmonary hypertension is highly prevalent in CPFE and is the leading determinant of death. Tobacco smoking has been proposed as the main factor in its etiology, though the pathophysiology and its natural history remain to be determined. High-resolution computed axial tomography is the mandatory tool to confirm the diagnosis. Currently, there is no consensus about its treatment since those published to date on this issue are limited to well-characterised series of cases; hence, a better understanding of this entity may help in the development of future therapeutic approaches.
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Lilburn, David M. L., Clémentine Lesbats, Joseph S. Six, Eric Dubuis, Liang Yew-Booth, Dominick E. Shaw, Maria G. Belvisi, Mark A. Birrell, Galina E. Pavlovskaya, and Thomas Meersmann. "Hyperpolarized 83 Kr magnetic resonance imaging of alveolar degradation in a rat model of emphysema." Journal of The Royal Society Interface 12, no. 107 (June 2015): 20150192. http://dx.doi.org/10.1098/rsif.2015.0192.
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Hyperpolarized 83 Kr surface quadrupolar relaxation (SQUARE) generates MRI contrast that was previously shown to correlate with surface-to-volume ratios in porous model surface systems. The underlying physics of SQUARE contrast is conceptually different from any other current MRI methodology as the method uses the nuclear electric properties of the spin I = 9/2 isotope 83 Kr. To explore the usage of this non-radioactive isotope for pulmonary pathophysiology, MRI SQUARE contrast was acquired in excised rat lungs obtained from an elastase-induced model of emphysema. A significant 83 Kr T 1 relaxation time increase in the SQUARE contrast was found in the elastase-treated lungs compared with the baseline data from control lungs. The SQUARE contrast suggests a reduction in pulmonary surface-to-volume ratio in the emphysema model that was validated by histology. The finding supports usage of 83 Kr SQUARE as a new biomarker for surface-to-volume ratio changes in emphysema.
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Kozma, Rodrigo de las Heras, Edson Marcelino Alves, Valter Abraao Barbosa-de-Oliveira, Fernanda Degobbi Tenorio Quirino dos Santos Lopes, Renan Cenize Guardia, Henrique Vivi Buzo, Carolina Arruda de Faria, et al. "A new experimental model of cigarette smoke-induced emphysema in Wistar rats." Jornal Brasileiro de Pneumologia 40, no. 1 (January 2014): 46–54. http://dx.doi.org/10.1590/s1806-37132014000100007.
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OBJECTIVE: To describe a new murine model of cigarette smoke-induced emphysema. METHODS: Twenty-four male Wistar rats were divided into two groups: the cigarette smoke group, comprising 12 rats exposed to smoke from 12 commercial filter cigarettes three times a day (a total of 36 cigarettes per day) every day for 30 weeks; and the control group, comprising 12 rats exposed to room air three times a day every day for 30 weeks. Lung function was assessed by mechanical ventilation, and emphysema was morphometrically assessed by measurement of the mean linear intercept (Lm). RESULTS: The mean weight gain was significantly (approximately ten times) lower in the cigarette smoke group than in the control group. The Lm was 25.0% higher in the cigarette smoke group. There was a trend toward worsening of lung function parameters in the cigarette smoke group. CONCLUSIONS: The new murine model of cigarette smoke-induced emphysema and the methodology employed in the present study are effective and reproducible, representing a promising and economically viable option for use in studies investigating the pathophysiology of and therapeutic approaches to COPD.
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Cappetta, Donato, Antonella De Angelis, Giuseppe Spaziano, Gioia Tartaglione, Elena Piegari, Grazia Esposito, Loreta Pia Ciuffreda, et al. "Lung Mesenchymal Stem Cells Ameliorate Elastase-Induced Damage in an Animal Model of Emphysema." Stem Cells International 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/9492038.
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Pulmonary emphysema is a respiratory condition characterized by alveolar destruction that leads to airflow limitation and reduced lung function. Although with extensive research, the pathophysiology of emphysema is poorly understood and effective treatments are still missing. Evidence suggests that mesenchymal stem cells (MSCs) possess the ability to engraft the injured tissues and induce repair via a paracrine effect. Thus, the aim of this study was to test the effects of the intratracheal administration of lung-derived mouse MSCs in a model of elastase-induced emphysema. Pulmonary function (static lung compliance) showed an increased stiffness induced by elastase, while morphometric findings (mean linear intercept and tissue/alveolar area) confirmed the severity of alveolar disruption. Contrarily, MSC administration partially restored lung elasticity and alveolar architecture. In the absence of evidence that MSCs acquired epithelial phenotype, we detected an increased proliferative activity of aquaporin 5- and surfactant protein C-positive lung cells, suggesting MSC-driven paracrine mechanisms. The data indicate the mediation of hepatocyte growth factor in amplifying MSC-driven tissue response after injury. Our study shed light on supportive properties of lung-derived MSCs, although the full identification of mechanisms orchestrated by MSCs and responsible for epithelial repair after injury is a critical aspect yet to be achieved.
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Ingenito, Edward P., Larry W. Tsai, Arnab Majumdar, and Bela Suki. "On the Role of Surface Tension in the Pathophysiology of Emphysema." American Journal of Respiratory and Critical Care Medicine 171, no. 4 (February 15, 2005): 300–304. http://dx.doi.org/10.1164/rccm.200406-770pp.
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Sasaki, Mamoru, Shotaro Chubachi, Naofumi Kameyama, Minako Sato, Mizuha Haraguchi, Masaki Miyazaki, Saeko Takahashi, and Tomoko Betsuyaku. "Evaluation of cigarette smoke-induced emphysema in mice using quantitative micro-computed tomography." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 10 (May 15, 2015): L1039—L1045. http://dx.doi.org/10.1152/ajplung.00366.2014.
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Chronic cigarette smoke (CS) exposure provokes variable changes in the lungs, and emphysema is an important feature of chronic obstructive pulmonary disease. The usefulness of micro-computed tomography (CT) to assess emphysema in different mouse models has been investigated, but few studies evaluated the dynamic structural changes in a CS-induced emphysema mouse model. A novel micro-CT technique with respiratory and cardiac gating has resulted in high-quality images that enable processing for further quantitative and qualitative analyses. Adult female C57BL/6J mice were repeatedly exposed to mainstream CS, and micro-CT scans were performed at 0, 4, 12, and 20 wk. Emphysema was also histologically quantified at each time point. Air-exposed mice and mice treated with intratracheal elastase served as controls and comparisons, respectively. End-expiratory lung volume, corresponding to functional residual volume, was defined as the calculated volume at the phase of end-expiration, and it evaluated air trapping. The end-expiratory lung volumes of CS-exposed mice were significantly larger than those of air controls at 12 and 20 wk, which was in line with alveolar enlargement and destruction by histological quantification. However, CS exposure neither increased low attenuation volume nor decreased the average lung CT value at any time point, unlike the elastase-instilled emphysema model. CS-exposed mice had rather higher average lung CT values at 4 and 12 wk. This is the first study characterizing a CS-induced emphysema model on micro-CT over time in mice. Moreover, these findings extend our understanding of the distinct pathophysiology of CS-induced emphysema in mice.
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Kopf, Katrina W., Julie W. Harral, Emily A. Staker, Megan E. Summers, Irina Petrache, Vitaly Kheyfets, David C. Irwin, and Susan M. Majka. "Optimization of combined measures of airway physiology and cardiovascular hemodynamics in mice." Pulmonary Circulation 10, no. 1 (January 2020): 204589402091293. http://dx.doi.org/10.1177/2045894020912937.
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Pulmonary hypertension may arise as a complication of chronic lung disease typically associated with tissue hypoxia, as well as infectious agents or injury eliciting a type 2 immune response. The onset of pulmonary hypertension in this setting (classified as Group 3) often complicates treatment and worsens prognosis of chronic lung disease. Chronic lung diseases such as chronic obstructive lung disease (COPD), emphysema, and interstitial lung fibrosis impair airflow and alter lung elastance in addition to affecting pulmonary vascular hemodynamics that may culminate in right ventricle dysfunction. To date, functional endpoints in murine models of chronic lung disease have typically been limited to separately measuring airway and lung parenchyma physiology. These approaches may be lengthy and require a large number of animals per experiment. Here, we provide a detailed protocol for combined assessment of airway physiology with cardiovascular hemodynamics in mice. Ultimately, a comprehensive overview of pulmonary function in murine models of injury and disease will facilitate the integration of studies of the airway and vascular biology necessary to understand underlying pathophysiology of Group 3 pulmonary hypertension.
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Le Rouzic, Olivier, Muriel Pichavant, Emilie Frealle, Antoine Guillon, Mustapha Si-Tahar, and Philippe Gosset. "Th17 cytokines: novel potential therapeutic targets for COPD pathogenesis and exacerbations." European Respiratory Journal 50, no. 4 (October 2017): 1602434. http://dx.doi.org/10.1183/13993003.02434-2016.
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Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways caused mainly by cigarette smoke exposure. COPD progression is marked by exacerbations of the disease, often associated with infections. Recent data show the involvement in COPD pathophysiology of interleukin (IL)-17 and IL-22, two cytokines that are important in the control of lung inflammation and infection. During the initiation and progression of the disease, increased IL-17 secretion causes neutrophil recruitment, leading to chronic inflammation, airways obstruction and emphysema. In the established phase of COPD, a defective IL-22 response facilitates pathogen-associated infections and disease exacerbations. Altered production of these cytokines involves a complex network of immune cells and dysfunction of antigen-presenting cells. In this review, we describe current knowledge on the involvement of IL-17 and IL-22 in COPD pathophysiology at steady state and during exacerbations, and discuss implications for COPD management and future therapeutic approaches.
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Pierre, Alexandre, Flora Lemaire, Aïda Meghraoui-Kheddar, Sandra Audonnet, Stéphanie Héry-Huynh, and Richard Le Naour. "Impact of aging on inflammatory and immune responses during elastin peptide-induced murine emphysema." American Journal of Physiology-Lung Cellular and Molecular Physiology 316, no. 4 (April 1, 2019): L608—L620. http://dx.doi.org/10.1152/ajplung.00402.2018.
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Deterioration of lung functions and degradation of elastin fibers with age are accelerated during chronic obstructive pulmonary disease (COPD). Excessive genesis of soluble elastin peptides (EP) is a key factor in the pathophysiology of COPD. We have previously demonstrated that 6-wk-old mice exhibited emphysematous structural changes associated with proinflammatory immune response after EP instillation. In this study, we investigated the consequences of aging on inflammatory, immune, and histological criteria associated with murine emphysema progression after EP exposure. Young (6 wk old) and elderly (15 mo old) C57BL/6J mice were endotracheally instilled with EP, and, at various time points after treatment, the inflammatory cell profiles from bronchoalveolar lavage fluids (BALF) and the T-lymphocyte phenotypes, at local and systemic levels, were analyzed by flow cytometry. Lungs were also prepared to allow morphological and histological analysis by confocal microscopy. Elderly mice exhibited an earlier development of pulmonary emphysema, characterized by an increase of the inflammatory and lymphocytic infiltrates, extracellular matrix breakdown, and airspace enlargement compared with young mice. This age-dependent parenchymal tissue remodeling was associated with an increase of the matrix metalloproteinase expressions and desmosine levels in BALF and/or sera of EP-treated mice. In addition, both the proportion of CD4+CD28− and CD8+CD28− T cells in the tissues of EP-treated mice and the interferon-γ levels in the EP-specific memory T-cell clones were significantly higher in elderly versus younger mice. This study demonstrates that aging accelerates emphysema development and that this effect is linked to increased EP production and their effects on inflammatory and immune response.
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Triantaphyllopoulos, Kostas, Farhana Hussain, Mariona Pinart, Min Zhang, Feng Li, Ian Adcock, Paul Kirkham, Jie Zhu, and Kian Fan Chung. "A model of chronic inflammation and pulmonary emphysema after multiple ozone exposures in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 300, no. 5 (May 2011): L691—L700. http://dx.doi.org/10.1152/ajplung.00252.2010.
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Oxidative stress plays a role in the pathophysiology of emphysema through the activation of tissue proteases and apoptosis. We examined the effects of ozone exposure by exposing BALB/c mice to either a single 3-h exposure or multiple exposures over 3 or 6 wk, with two 3-h exposures per week. Compared with air-exposed mice, the increase in neutrophils in bronchoalveolar lavage fluid and lung inflammation index was greatest in mice exposed for 3 and 6 wk. Lung volumes were increased in 3- and 6-wk-exposed mice but not in single-exposed. Alveolar space and mean linear intercept were increased in 6- but not 3-wk-exposed mice. Caspase-3 and apoptosis protease activating factor-1 immunoreactivity was increased in the airway and alveolar epithelium and macrophages of 3- and 6-wk-exposed mice. Interleukin-13, keratinocyte chemoattractant, caspase-3, and IFN-γ mRNA were increased in the 6-wk-exposed group, but heme oxygenase-1 (HO-1) mRNA decreased. matrix metalloproteinase-12 (MMP-12) and caspase-3 protein expression increased in lungs of 6-wk-exposed mice. Collagen area increased and epithelial area decreased in airway wall at 3- and 6-wk exposure. Exposure of mice to ozone for 6 wk induced a chronic inflammatory process, with alveolar enlargement and damage linked to epithelial apoptosis and increased protease expression.
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Vlahos, Ross, and Steven Bozinovski. "Recent advances in pre-clinical mouse models of COPD." Clinical Science 126, no. 4 (October 14, 2013): 253–65. http://dx.doi.org/10.1042/cs20130182.
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COPD (chronic obstructive pulmonary disease) is a major incurable global health burden and will become the third largest cause of death in the world by 2020. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T-cells are prominent, leads to oxidative stress, emphysema, small airways fibrosis and mucus hypersecretion. The mechanisms and mediators that drive the induction and progression of chronic inflammation, emphysema and altered lung function are poorly understood. Current treatments have limited efficacy in inhibiting chronic inflammation, do not reverse the pathology of disease and fail to modify the factors that initiate and drive the long-term progression of disease. Therefore there is a clear need for new therapies that can prevent the induction and progression of COPD. Animal modelling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies. The present review highlights some of the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and whether they can be used to predict the efficacy of new therapeutics for COPD.
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Hao, Wendong, Manxiang Li, Yunqing Zhang, Cailian Zhang, and Ping Wang. "Severity of chronic obstructive pulmonary disease with ‘exacerbator with emphysema phenotype’ is associated with potential biomarkers." Postgraduate Medical Journal 96, no. 1131 (August 2, 2019): 28–32. http://dx.doi.org/10.1136/postgradmedj-2019-136599.
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ObjectiveThe present study was designed to investigate the biomarkers levels of fractalkine (FKN), neutrophil elastase (NE) and matrix metalloproteinase-12 (MMP-12) in chronic obstructive pulmonary disease (COPD) with ‘exacerbator with emphysema phenotype’ and to evaluate the associations between the biomarkers levels and the severity of disease by spirometric measurements.MethodsA total of 84 COPD patients and 49 healthy controls were enrolled in our study. ELISA were utilised to detect the FKN, MMP-12 and NE in serum from all subjects.ResultsFKN (p<0.001), NE (p=0.039) and MMP-12 (p<0.001) in serum of COPD patients showed higher levels than that of healthy control subjects. Serum FKN (p<0.001), MMP-12 (p<0.001) and NE (p=0.043) levels were significantly higher in severe and very severe COPD patients than that in mild and moderate COPD patients. Circulating FKN, MMP-12 and NE expression levels were significantly elevated (p<0.001) in COPD smokers compared with COPD non-smokers. The smoke pack years were negatively correlated with FEV1%pred (r=−0.5036), FEV1/FVC ratio (r=−0.2847) (FEV, forced expiratory volume; FVC, forced vital capacity). Similarly, we observed a strong positive correlation between the smoke pack years and serum levels of FKN (r=0.4971), MMP-12 (r=0.4315) and NE (r=0.2754). FEV1%pred was strongly negatively correlated with cytokine levels of FKN (r=−0.4367), MMP-12 (r=−0.3295) and NE (r=−0.2684). Likewise, FEV1/FVC ratio was negatively correlated with mediators of inflammation levels of FKN (r=−0.3867), MMP-12 (r=−0.2941) and NE (r=−0.2153).ConclusionSerum FKN, MMP-12 and NE concentrations in COPD patients are directly associated with the severity of COPD with ‘exacerbator with emphysema phenotype’. This finding suggests that FKN, MMP-12 and NE might play an important role in the pathophysiology of COPD.
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Shimizu, Kaoruko, Satoshi Konno, Hironi Makita, Hirokazu Kimura, Hiroki Kimura, Masaru Suzuki, and Masaharu Nishimura. "Transfer coefficients better reflect emphysematous changes than carbon monoxide diffusing capacity in obstructive lung diseases." Journal of Applied Physiology 125, no. 1 (July 1, 2018): 183–89. http://dx.doi.org/10.1152/japplphysiol.01062.2017.
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The overlap between asthma and chronic obstructive pulmonary disease (COPD) has attracted the interest of pulmonary physicians; thus, measurement of carbon monoxide diffusion capacity (DLco) and/or transfer coefficients (Kco, DLco/VA) may become valuable in clinical settings. How these parameters behave in chronic obstructive lung diseases is poorly understood. We predicted that Kco might more accurately reflect emphysematous changes in the lungs than DLco. We examined DLco and Kco in nonsmokers and smokers with asthma and investigated their relationships with forced expiratory volume in 1 s (%FEV1) by group. We then selected nonsmokers (As-NS) and smokers with asthma (As-Sm) in both groups and those with COPD while controlling for the degree of airflow limitation across groups. Emphysema volumes [%lung attenuation volume (%LAV)] and percentage of cross-sectional area of small pulmonary vessels <5 mm2 (%CSA<5) were measured by computed tomography. In As-NS, %Kco was significantly higher when FEV1% was reduced, but such a correlation was not seen in As-Sm. %Kco successfully differentiated among the three groups when airflow limitation levels were matched. However, %DLc, was significantly reduced only in patients with COPD. Both %LAV and %CSA<5 were better correlated with %Kco than with %DLco. There was discordance between %DLCO and %Kco in As-Sm, which was not seen in As-NS. Overall, %Kco better reflects emphysematous changes in obstructive lung diseases than %DLco. NEW & NOTEWORTHY Despite differing behaviors of %Kco and %DLco in several diseases, the characteristics of these parameters have not been fully examined in smokers with asthma. Here, we demonstrated that %Kco is a more sensitive parameter of pathophysiology, better reflecting emphysematous changes in chronic obstructive lung diseases overall, compared with %DLco. Thus, more precise interpretations of %DLco and %Kco may provide clues for understanding the pathophysiology of obstructive lung diseases.
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Braber, Saskia, Pim J. Koelink, Paul A. J. Henricks, Patricia L. Jackson, Frans P. Nijkamp, Johan Garssen, Aletta D. Kraneveld, J. Edwin Blalock, and Gert Folkerts. "Cigarette smoke-induced lung emphysema in mice is associated with prolyl endopeptidase, an enzyme involved in collagen breakdown." American Journal of Physiology-Lung Cellular and Molecular Physiology 300, no. 2 (February 2011): L255—L265. http://dx.doi.org/10.1152/ajplung.00304.2010.
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There is increasing evidence that the neutrophil chemoattractant proline-glycine-proline (PGP), derived from the breakdown of the extracellular matrix, plays an important role in neutrophil recruitment to the lung. PGP formation is a multistep process involving neutrophils, metalloproteinases (MMPs), and prolyl endopeptidase (PE). This cascade of events is now investigated in the development of lung emphysema. A/J mice were whole body exposed to cigarette smoke for 20 wk. After 20 wk or 8 wk after smoking cessation, animals were killed, and bronchoalveolar lavage fluid and lung tissue were collected to analyze the neutrophilic airway inflammation, the MMP-8 and MMP-9 levels, the PE activity, and the PGP levels. Lung tissue degradation was assessed by measuring the mean linear intercept. Additionally, we investigated the effect of the peptide l-arginine-threonine-arginine (RTR), which binds to PGP sequences, on the smoke-induced neutrophil influx in the lung after 5 days of smoke exposure. Neutrophilic airway inflammation was induced by cigarette smoke exposure. MMP-8 and MMP-9 levels, PE activity, and PGP levels were elevated in the lungs of cigarette smoke-exposed mice. PE was highly expressed in epithelial and inflammatory cells (macrophages and neutrophils) in lung tissue of cigarette smoke-exposed mice. After smoking cessation, the neutrophil influx, the MMP-8 and MMP-9 levels, the PE activity, and the PGP levels were decreased or reduced to normal levels. Moreover, RTR inhibited the smoke-induced neutrophil influx in the lung after 5 days' smoke exposure. In the present murine model of cigarette smoke-induced lung emphysema, it is demonstrated for the first time that all relevant components (neutrophils, MMP-8, MMP-9, PE) involved in PGP formation from collagen are upregulated in the airways. Together with MMPs, PE may play an important role in the formation of PGP and thus in the pathophysiology of lung emphysema.
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Stadler, Alfred, Leopold Stiebellehner, Peter M. Jakob, Johannes F. T. Arnold, Edith Eisenhuber, Isabella von Katzler, and Alexander A. Bankier. "Quantitative and O2Enhanced MRI of the Pathologic Lung: Findings in Emphysema, Fibrosis, and Cystic Fibrosis." International Journal of Biomedical Imaging 2007 (2007): 1–7. http://dx.doi.org/10.1155/2007/23624.
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Purpose: beyond the pure morphological visual representation, MR imaging offers the possibility to quantify parameters in the healthy, as well as, in pathologic lung parenchyma. Gas exchange is the primary function of the lung and the transport of oxygen plays a key role in pulmonary physiology and pathophysiology. The purpose of this review is to present a short overview of the relaxation mechanisms of the lung and the current technical concepts of T1 mapping and methods of oxygen enhanced MR imaging.Material and Methods: molecular oxygen has weak paramagnetic properties so that an increase in oxygen concentration results in shortening of the T1 relaxation time and thus to an increase of the signal intensity in T1 weighted images. A possible way to gain deeper insights into the relaxation mechanisms of the lung is the calculation of parameter Maps. T1 Maps based on a snapshot FLASH sequence obtained during the inhalation of various oxygen concentrations provide data for the creation of the so-called oxygen transfer function (OTF), assigning a measurement for local oxygen transfer. T1 weighted single shot TSE sequences also permit expression of the signal changing effects associated with the inhalation of pure oxygen.Results: the average of the mean T1 values over the entire lung in inspiration amounts to 1199+/−117 milliseconds, the average of the mean T1 values in expiration was 1333+/−167 milliseconds. T1 Maps of patients with emphysema and lung fibrosis show fundamentally different behavior patterns. Oxygen enhanced MRT is able to demonstrate reduced diffusion capacity and diminished oxygen transport in patients with emphysema and cystic fibrosis.Discussion: results published in literature indicate that T1 mapping and oxygen enhanced MR imaging are promising new methods in functional imaging of the lung and when evaluated in conjunction with the pure morphological images can provide additional valuable information.
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Sinden, Nicola J., Michael J. Baker, David J. Smith, Jan-Ulrich Kreft, Timothy R. Dafforn та Robert A. Stockley. "α-1-Antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease". American Journal of Physiology-Lung Cellular and Molecular Physiology 308, № 2 (15 січня 2015): L179—L190. http://dx.doi.org/10.1152/ajplung.00179.2014.
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The excessive activities of the serine proteinases neutrophil elastase and proteinase 3 are associated with tissue damage in chronic obstructive pulmonary disease. Reduced concentrations and/or inhibitory efficiency of the main circulating serine proteinase inhibitor α-1-antitrypsin result from point mutations in its gene. In addition, α-2-macroglobulin competes with α-1-antitrypsin for proteinases, and the α-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of α-1-antitrypsin mutations on this partitioning. Subsequently, we have developed a three-dimensional reaction-diffusion model to describe events occurring in the lung interstitium when serine proteinases diffuse from the neutrophil azurophil granule following degranulation and subsequently bind to either α-1-antitrypsin or α-2-macroglobulin. We found that the proteinases remained uninhibited on the order of 0.1 s after release and diffused on the order of 10 μm into the tissue before becoming sequestered. We have shown that proteinases sequestered to α-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with α-2-macroglobulin are able to degrade elastin. Although neutrophil elastase is implicated in the pathophysiology of emphysema, our results highlight a potentially important role for proteinase 3 because of its greater concentration in azurophil granules, its reduced association rate constant with all α-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to α-2-macroglobulin where it retains proteolytic activity.
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Kim, Yun-Ho, Min-Kyung Kang, Eun-Jung Lee, Dong Yeon Kim, Hyeongjoo Oh, Soo-Il Kim, Su Yeon Oh, et al. "Astragalin Inhibits Cigarette Smoke-Induced Pulmonary Thrombosis and Alveolar Inflammation and Disrupts PAR Activation and Oxidative Stress-Responsive MAPK-Signaling." International Journal of Molecular Sciences 22, no. 7 (April 1, 2021): 3692. http://dx.doi.org/10.3390/ijms22073692.
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Epidemiological evidence shows that smoking causes a thrombophilic milieu that may play a role in the pathophysiology of chronic obstructive pulmonary disease (COPD) as well as pulmonary thromboembolism. The increased nicotine level induces a prothrombotic status and abnormal blood coagulation in smokers. Since several anticoagulants increase bleeding risk, alternative therapies need to be identified to protect against thrombosis without affecting hemostasis. Astragalin is a flavonoid present in persimmon leaves and green tea seeds and exhibits diverse activities of antioxidant and anti-inflammation. The current study investigated that astragalin attenuated smoking-induced pulmonary thrombosis and alveolar inflammation. In addition, it was explored that molecular links between thrombosis and inflammation entailed protease-activated receptor (PAR) activation and oxidative stress-responsive mitogen-activated protein kinase (MAPK)-signaling. BALB/c mice were orally administrated with 10–20 mg/kg astragalin and exposed to cigarette smoke for 8 weeks. For the in vitro study, 10 U/mL thrombin was added to alveolar epithelial A549 cells in the presence of 1–20 µM astragalin. The cigarette smoking-induced the expression of PAR-1 and PAR-2 in lung tissues, which was attenuated by the administration of ≥10 mg/kg astragalin. The oral supplementation of ≥10 mg/kg astragalin to cigarette smoke-challenged mice attenuated the protein induction of urokinase plasminogen activator, plasminogen activator inhibitor-1and tissue factor, and instead enhanced the induction of tissue plasminogen activator in lung tissues. The astragalin treatment alleviated cigarette smoke-induced lung emphysema and pulmonary thrombosis. Astragalin caused lymphocytosis and neutrophilia in bronchoalveolar lavage fluid due to cigarette smoke but curtailed infiltration of neutrophils and macrophages in airways. Furthermore, this compound retarded thrombin-induced activation of PAR proteins and expression of inflammatory mediators in alveolar cells. Treating astragalin interrupted PAR proteins-activated reactive oxygen species production and MAPK signaling leading to alveolar inflammation. Accordingly, astragalin may interrupt the smoking-induced oxidative stress–MAPK signaling–inflammation axis via disconnection between alveolar PAR activation and pulmonary thromboembolism.
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Nichols, Larry, Rachel Saunders, and Friedrich D. Knollmann. "Causes of Death of Patients With Lung Cancer." Archives of Pathology & Laboratory Medicine 136, no. 12 (December 1, 2012): 1552–57. http://dx.doi.org/10.5858/arpa.2011-0521-oa.
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Context.—The causes of death for patients with lung cancer are inadequately described. Objective.—To categorize the immediate and contributing causes of death for patients with lung cancer. Design.—The autopsies from 100 patients who died of lung cancer between 1990 and February 2011 were analyzed. Results.—Tumor burden was judged the immediate cause of death in 30 cases, including 26 cases of extensive metastases and 4 cases with wholly or primarily lung tumor burden (causing respiratory failure). Infection was the immediate cause of death for 20 patients, including 8 with sepsis and 12 with pneumonia. Complications of metastatic disease were the immediate causes of death in 18 cases, including 6 cases of hemopericardium from pericardial metastases, 3 from myocardial metastases, 3 from liver metastases, and 3 from brain metastases. Other immediate causes of death were pulmonary hemorrhage (12 cases), pulmonary embolism (10 cases, 2 tumor emboli), and pulmonary diffuse alveolar damage (7 cases). From a functional (pathophysiologic) perspective, respiratory failure could be regarded as the immediate cause of death (or mechanism of death) in 38 cases, usually because of a combination of lung conditions, including emphysema, airway obstruction, pneumonia, hemorrhage, embolism, resection, and lung injury in addition to the tumor. For 94 of the 100 patients, there were contributing causes of death, with an average of 2.5 contributing causes and up to 6 contributing causes of death. Conclusions.—The numerous and complex ways lung cancer kills patients pose a challenge for efforts to extend and improve their lives.
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Kumar, S., S. K. Sharma, B. Medhi, and K. L. Khanduja. "Therapeutic Potential of Cytosolic PLA2 Isoform–Specific Inhibitor Arachidonyl Trifluromethyl Ketone in Cigarette Smoke Condensate–Induced Pathological Conditions in Alveolar Type I and II Epithelial Cells." Journal of Global Oncology 4, Supplement 2 (October 1, 2018): 221s. http://dx.doi.org/10.1200/jgo.18.89300.
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Background: Cigarette smoking is responsible for various lung pathologies including chronic lung inflammation, emphysema, chronic obstructive pulmonary disease (COPD), cancer, and annually causes almost 10 million deaths globally. During smoke exposure, most affected cells are the alveolar epithelial cells where as a repair mechanism, activation of cytosolic phospholipase A2 enzymes takes place. High free radicals and cPLA2 activity due to continuous exposure of smoke exposure leads to elevated levels of secondary metabolites and various pathophysiologic conditions such as chronic inflammation, oxidative stress and cancer. To reduce the burden of chronic inflammation as well as oxidative stress, and higher levels of secondary metabolites whose role is well defined in progression of cancer, we checked the therapeutic potential of cPLA2 inhibitor arachidonyl trifluromethyl ketone (ATK) by pharmacologically targeting the most expressible cPLA2 during continuous exposure of cigarette smoke. Aim: To check the therapeutic potential of cytosolic PLA2 isoform specific inhibitor arachidonyl trifluromethyl ketone in cigarette smoke condensate–induced pathologic conditions in alveolar type I and II epithelial cells. Methods: Effect of cPLA2 inhibitor on CSC-induced cPLA2 activity were checked using colorimetric assay, cell viability using MTT assay, FDA uptake assay using fluorescence microscopy, ROS levels and apoptosis markers through flow cytometry, and ERK levels using ELISA, in both type of alveolar epithelial cells. Results: ATK significantly mimicked CSC-induced cPLA2 activity, free radicals, primary apoptosis, ratio of apoptotic/apoptotic proteins and levels of ERK whereas protected cells from loss of cell viability and membrane integrity. Conclusion: Current observations revealed cPLA2s as a potential therapeutic target and their inhibitor ATK as a potential therapeutic agent in Cigarette smoke induced pathological conditions in alveolar type I and II epithelial cells.
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Ivovic, Miomira, Biljana Radojkovic, Zorana Penezic, Mirjana Stojkovic, Milina Tancic, Svetlana Vujovic, Andrija Bogdanovic, and Milka Drezgic. "Agranulocytosis and acute coronary syndrom in apathetic hyperthyreoidism." Srpski arhiv za celokupno lekarstvo 131, no. 5-6 (2003): 249–53. http://dx.doi.org/10.2298/sarh0306249i.
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INTRODUCTION Tissue expose to excessive levels of circulating thyroid hormones results in thyrotoxicosis. In most cases, thyrotoxicosis is due to hyper-activity of the thyroid gland. Cardiovascular and myopathic manifestations are predominant clinical features in most hyperthyroid patients, aged 60 years and older. Some of patients have apathetic hyperthyreoidism which presents with weight loss, small goiter, severe depression and without clinical features of increased sympathetic activity [3, 6]. About 50% of patients with cardiovascular manifestations have no evidence of underlying heart disease. Cardiac problems resolve when euthyreoid state is established [3]. Three treatment modalities are available in hyperthyreodism, namely medicament therapy, surgery and radioactive iodine. Antithyroid drug therapy complications, can be mild such as rash, which is managed without cessation of therapy by antihistamines administration. On the other hand, very serious complications such as agranulocytosis, necessitate immediate discontinuation of the medication and appropriate treatment. Although extremely rear, it is life-threatening with highly variable recovery time. CASE REPORT A 62-year-old woman with recurrent hyperthyroidism was admitted after treatment of agranu locytosis due to antithyroid drugs in another institution with G-CSF. The patient presented with clinical features of apathetic hyperthyroidism with extremely elevated thyroid hormone levels (total and free T4) and suppressed TSH. Radioactive iodine (5 mCi) was administered after increased thyroid uptake was confirmed. Echocardiography on admission was normal. ECG revealed moderately inverted T waves in standard and V1, V2 precordial leads. Laboratory analysis revealed mild normocytic anemia with normal white blood cell count, hypokaliemia and normal concentration of creatine phosphokinase lactic dehidrogenase and mildly elevated aspartate transaminase in sera. Chest X-ray was consistent with pulmonary emphysema. Because the worsening of ECG changes she was transferred to Coronary unit. The diagnosis of non-Q myocardial infarction was confirmed and treatment with nitrates and beta-adrenergic antagonists was instituted. Four weeks later she became euthyroid and coronarography was performed. Subepicardial coronary arteries were normal (Figure 1). She was dismissed, and still euthyroid three months later. DISCUSSION Agranulocytosis is very rare but very serious complication of antithyroid drug therapy. It can be detected in about 0.1 -1 % patients during the first three months of treatment. Sudden appearance, heralded by sore throat and fever, prompt physicians to seek white blood cell and differential count [1-3]. Confirmation of diagnosis urges cessation of drug therapy and appropriate antibiotic treatment. Recently, it was reported that recombinant human granulocyte colony-stimulating factor (rhG-CSF) is to be effective in shortening the recovery time in the neutropenic patients undergoing chemotherapy and also in patients with other types of neutropenia [5]. Tamai at al. [7] confirmed positive outcome in 34 patients treated with rhG-CSF compared to corticosteroid treatment. Hematologic laboratory abnormalities disappear 7-10 days after secession of therapy. Patients completely recover two to three weeks later. Fatal outcome was also described [1 -5]. Thyroid hormones have profound effects on cardiovascular physiology, especially on heart rate, cardiac output and systemic vascular resistance. In patients with hyperthyroidism, cardiac output is much higher than in normal persons. This is the result of direct effect of thyroid hormones on cardiac muscle contractility, heart rate and decrease in systemic vascular resistance. Excessive thyroid hormone secretion increases cardiac Na-K-activated plasma membrane ATP-ase and sarcoplasmic reticulum Ca-activated ATP-ase with resultant in increase myocardial contractility [6 9]. Sinus tachycardia is the most common rhythm disorder in hyperthyroidism but paroxysmal tachycardia and atrial fibrillation are not rare. This can be explained by increased heart rate, cardiac output, blood volume, coronary artery flow and peripheral oxygen consumption in thyreotoxicosis [9]. Patients with coronary arteriosclerosis can develop angina pectoris during thyreotoxic stage, which can be explained by imbalance between cardiac demand and supply. Myocardial damage is often in thyrotoxic patients with chronic hart failure, together with myocardial infarction in patients without coronary disease [2,6]. Congestive heart failure and atrial fibrillation are relatively resistant to digitalis treatment because of high metabolic turn over of medication and excessive myocardial irritability in hyperthyro-idism [6]. Cardiovascular and myopathic manifestations predominate in older hyperthyroid patients (over 60 years) and some of them can have only few symptoms of hyperthyroidism [1-3]. Thyrotoxic state characterized by fatigue, apathy, extreme weakness, low-grade fever and sometimes congestive heart failure are designated as apathetic hyperthyroidism. Such patients have small goiters, mild tachycardia and often cool and dry skin with few eye signs [6]. Patients with subclinical hyperthyroidism are at increased risk for atrial fibrillation [9]. Unstable angina and non-Q myocardial infarction (non ST elevation) are acute manifestation of coronary artery disease. The acute coronary syndrome of unstable angina, non-Q myocardial infarction and Q-wave myocardial infarction have atherosclerotic lesions of the coronary arteries as a common pathogenic substrate. Errosions or ruptures of unstable atherosclerotic plaque triggered pathophysiologic processes, resulted in thrombus formation at the site of arterial injury. This leads to abrupt reduction or cessation through the affected vessel. Clinical manifestations of unstable angina and non-Q myocardial infarction are similar and diagnosis of non-Q myocardial infarction is made on the basis of elevated serum markers indicative of cardiac necrosis, detected in peripheral circulation. Acute coronary syndrome ranging from unstable angina to myocardial infarction an non-Q myocardial infarction represents increasingly severe manifestations of the same pathophysiologic processes [10,11]. In conclusion, these 62-year-old woman presented with apathetic form of recurrent hyperthyroidism associated with two serious complications life-threatening agranulocytosis and acute coronary syndrome.
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Marsh, Regan H. "Chronic Obstructive Pulmonary Disease." DeckerMed Emergency Medicine, February 1, 2017. http://dx.doi.org/10.2310/em.4208.
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Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow obstruction that is not fully reversible. The airflow obstruction is usually progressive and associated with an inflammatory response of the lungs to noxious particles and gases, often from smoking. COPD is the third leading cause of death in the United States, with both its prevalence and mortality continuing to increase. It has also become one of the leading causes of death and disability worldwide. COPD is estimated to affect more than 5% of the total population in the United States; approximately 5 million adults have emphysema and another 10 million have chronic bronchitis. This review covers the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes of COPD. Figures show spirometry test results in a normal patient and a patient with severe COPD, stages of COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the pathogenesis of emphysema from smoking, pathologic lesions in small airways in a patient with COPD, the acinar structure of normal lungs compared with that of lungs in patients with centriacinar (centrilobular) emphysema or panacinar (panlobular) emphysema, and electrocardiogram demonstrating findings consistent with P pulmonale and right heart strain due to advanced COPD. Tables list pathogenic mechanisms of COPD, pathophysiology of a COPD exacerbation, bacterial pathogens in acute COPD exacerbations, key historical features of COPD, differential diagnosis of patients presenting with possible COPD, criteria for hospitalization as indicated by GOLD guidelines, and indications for ICU admission. This review contains 6 highly rendered figures, 7 tables, and 124 references Key words: Chronic obstructive pulmonary disease; COPD; Emphysema; Chronic bronchitis; Acute exacerbation of COPD; AECOPD; Airway disease
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Tripathi, Lokesh P., Mari N. Itoh, Yoshito Takeda, Kazuyuki Tsujino, Yasushi Kondo, Atsushi Kumanogoh, and Kenji Mizuguchi. "Integrative Analysis Reveals Common and Unique Roles of Tetraspanins in Fibrosis and Emphysema." Frontiers in Genetics 11 (December 10, 2020). http://dx.doi.org/10.3389/fgene.2020.585998.
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While both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are multifactorial disorders characterized by distinct clinical and pathological features, their commonalities and differences have not been fully elucidated. We sought to investigate the preventive roles of tetraspanins Cd151 and Cd9 -that are involved in diverse cellular processes in lung pathophysiology- in pulmonary fibrosis and emphysema, respectively, and to obtain a deeper understanding of their underlying molecular mechanisms toward facilitating improved therapeutic outcomes. Using an integrative approach, we examined the transcriptomic changes in the lungs of Cd151- and Cd9-deficient mice using functional-enrichment-analysis, pathway-perturbation-analysis and protein-protein-interaction (PPI) network analysis. Circadian-rhythm, extracellular-matrix (ECM), cell-adhesion and inflammatory responses and associated factors were prominently influenced by Cd151-deletion. Conversely, cellular-junctions, focal-adhesion, vascular-remodeling, and TNF-signaling were deeply impacted by Cd9-deletion. We also highlighted a “common core” of factors and signaling cascades that underlie the functions of both Cd151 and Cd9 in lung pathology. Circadian dysregulation following Cd151-deletion seemingly facilitated progressive fibrotic lung phenotype. Conversely, TGF-β signaling attenuation and TNF-signaling activation emerged as potentially novel functionaries of Cd9-deletion-induced emphysema. Our findings offer promising avenues for developing novel therapeutic treatments for pulmonary fibrosis and emphysema.
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Kang, Ji Hee, Jiwoong Choi, Kum Ju Chae, Kyung Min Shin, Chang-Hoon Lee, Junfeng Guo, Ching-Long Lin, Eric A. Hoffman, and Changhyun Lee. "CT-derived 3D-diaphragm motion in emphysema and IPF compared to normal subjects." Scientific Reports 11, no. 1 (July 21, 2021). http://dx.doi.org/10.1038/s41598-021-93980-5.
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AbstractImage registration-based local displacement analysis enables evaluation of respiratory motion between two computed tomography-captured lung volumes. The objective of this study was to compare diaphragm movement among emphysema, idiopathic pulmonary fibrosis (IPF) and normal subjects. 29 normal, 50 emphysema, and 51 IPF subjects were included. A mass preserving image registration technique was used to compute displacement vectors of local lung regions at an acinar scale. Movement of the diaphragm was assumed to be equivalent to movement of the basal lung within 5 mm from the diaphragm. Magnitudes and directions of displacement vectors were compared between the groups. Three-dimensional (3D) and apico-basal displacements were smaller in emphysema than normal subjects (P = 0.003, P = 0.002). Low lung attenuation area on expiration scan showed significant correlations with decreased 3D and apico-basal displacements (r = − 0.546, P < 0.0001; r = − 0.521, P < 0.0001) in emphysema patients. Dorsal–ventral displacement was smaller in IPF than normal subjects (P < 0.0001). The standard deviation of the displacement angle was greater in both emphysema and IPF patients than normal subjects (P < 0.0001). In conclusion, apico-basal movement of the diaphragm is reduced in emphysema while dorsal–ventral movement is reduced in IPF. Image registration technique to multi-volume CT scans provides insight into the pathophysiology of limited diaphragmatic motion in emphysema and IPF.
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Khiroya, Heena, and Alice M. Turner. "The role of iron in pulmonary pathology." Multidisciplinary Respiratory Medicine 10 (December 20, 2019). http://dx.doi.org/10.4081/mrm.2015.337.
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Respiratory disease accounts for a large proportion of emergency admissions to hospital and diseaseassociated mortality. Genetic association studies demonstrate a link between iron metabolism and pulmonary disease phenotypes. IREB2 is a gene that produces iron regulatory protein 2 (IRP2), which has a key role in iron homeostasis. This review addresses pathways involved in iron metabolism, particularly focusing on the role of IREB2 . In addition to this, environmental factors also influence phenotypic variation in respiratory disease, for example inhaled iron from cigarette smoke is deposited in the lung and causes tissue damage by altering iron homeostasis. The effects of cigarette smoke are detailed in this article, particularly in relation to lung conditions that favour the upper lobes, such as emphysema and lung cancer. Clinical applications of iron homeostasis are also discussed in this review, especially looking at the pathophysiology of chronic obstructive pulmonary disease, lung cancer, pulmonary infections and acute respiratory distress syndrome. Promising new treatments involving iron are also covered.
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Dunican, Eleanor M., Brett M. Elicker, Travis Henry, David S. Gierada, Mark L. Schiebler, Wayne Anderson, Igor Barjaktarevic, et al. "Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers." American Journal of Respiratory and Critical Care Medicine, November 12, 2020. http://dx.doi.org/10.1164/rccm.202006-2248oc.
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Cárdenes, Nayra, John Sembrat, Kentaro Noda, Tyler Lovelace, Diana Álvarez, Humberto E. Trejo Bittar, Brian J. Philips, et al. "Human ex vivo lung perfusion: a novel model to study human lung diseases." Scientific Reports 11, no. 1 (January 12, 2021). http://dx.doi.org/10.1038/s41598-020-79434-4.
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AbstractExperimental animal models to predict physiological responses to injury and stress in humans have inherent limitations. Therefore, the development of preclinical human models is of paramount importance. Ex vivo lung perfusion (EVLP) has typically been used to recondition donor lungs before transplantation. However, this technique has recently advanced into a model to emulate lung mechanics and physiology during injury. In the present study, we propose that the EVLP of diseased human lungs is a well-suited preclinical model for translational research on chronic lung diseases. Throughout this paper, we demonstrate this technique's feasibility in pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), emphysema, and non-disease donor lungs not suitable for transplantation. In this study, we aimed to perfuse the lungs for 6 h with the EVLP system. This facilitated a robust and continuous assessment of airway mechanics, pulmonary hemodynamics, gas exchange, and biochemical parameters. We then collected at different time points tissue biopsies of lung parenchyma to isolate RNA and DNA to identify each disease's unique gene expression. Thus, demonstrating that EVLP could successfully serve as a clinically relevant experimental model to derive essential insights into pulmonary pathophysiology and various human lung diseases.
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Stewart, Neil J., Laurie J. Smith, Ho-Fung Chan, James A. Eaden, Smitha Rajaram, Andrew J. Swift, Nicholas D. Weatherley, et al. "Lung MRI with hyperpolarised gases: current & future clinical perspectives." British Journal of Radiology, June 9, 2021, 20210207. http://dx.doi.org/10.1259/bjr.20210207.
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The use of pulmonary MRI in a clinical setting has historically been limited. Whilst CT remains the gold-standard for structural lung imaging in many clinical indications, technical developments in ultrashort and zero echo time MRI techniques are beginning to help realise non-ionising structural imaging in certain lung disorders. In this invited review, we discuss a complementary technique – hyperpolarised (HP) gas MRI with inhaled 3He and 129Xe – a method for functional and microstructural imaging of the lung that has great potential as a clinical tool for early detection and improved understanding of pathophysiology in many lung diseases. HP gas MRI now has the potential to make an impact on clinical management by enabling safe, sensitive monitoring of disease progression and response to therapy. With reference to the significant evidence base gathered over the last two decades, we review HP gas MRI studies in patients with a range of pulmonary disorders, including COPD/emphysema, asthma, cystic fibrosis, and interstitial lung disease. We provide several examples of our experience in Sheffield of using these techniques in a diagnostic clinical setting in challenging adult and paediatric lung diseases.
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Pouwels, Simon D., Laura Hesse, Xinhui Wu, Venkata Sita Rama Raju Allam, Daan van Oldeniel, Linsey J. Bhiekharie, Simon Phipps, et al. "LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE." American Journal of Physiology-Lung Cellular and Molecular Physiology, August 18, 2021. http://dx.doi.org/10.1152/ajplung.00138.2021.
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The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. Additionally, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1, induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 hours, with stronger effects in a mouse strain susceptible for emphysema compared to a non-susceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.
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Esteve-Codina, Anna, Thomas P. Hofer, Dorothe Burggraf, Marion S. Heiss-Neumann, Wolfgang Gesierich, Anne Boland, Robert Olaso, et al. "Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes." Scientific Reports 11, no. 1 (June 18, 2021). http://dx.doi.org/10.1038/s41598-021-91742-x.
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AbstractChronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term “response to bacterium” was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term “response to stress” was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.
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Dirjayanto, Valerie Josephine. "Evidence on the Efficacy of Omega-3 Polyunsaturated Fatty Acids as an Adjunct Therapy for Chronic Obstructive Pulmonary Disease." Journal of Asian Medical Students' Association 9, no. 1 (September 4, 2021). http://dx.doi.org/10.52629/jamsa.v9i1.238.
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Background: As the fourth leading cause of death worldwide, Chronic Obstructive Pulmonary Disease (COPD) places a significant burden on healthcare-related costs. COPD is characterized by airflow impairment, including chronic bronchitis, small airways obstruction, and emphysema. COPD pathophysiology involves inflammation correlated with lung decline, body composition alteration, and decreased quality of life. Since preceding studies have shown its roles in inflammatory processes, omega-3 is proposed as a potential adjunct treatment in slowing down COPD progression.Aim: To analyse the efficacy of omega-3 as a potential adjunct therapy in COPD management.Method: A literature review was conducted by retrieving studies published from 2010-2020 through PubMed, EBSCOhost, Cochrane Controlled Register of Trials (CENTRAL), Scopus, Clinical Key, Wiley, and Science Direct that evaluate the effect of omega-3 supplementation in COPD management.Outcome: The search yielded 12 studies with a total of 6,474 subjects. Outcomes suggested that omega-3 leads to a reduction in inflammation, improved body composition, enhanced exercise capacity, higher quality of life, and lower exacerbation occurrences. Association found for lung function was weak, but this might be due to the study designs. The only potential adverse effect was diarrhoea, but this is insignificant.Conclusion: To conclude, omega-3 supplementation in COPD management showed promising results, considering its efficacy in slowing down COPD progression, minimal side effects, cost-effectiveness, and feasibility. However, the incorporation of this intervention into management guidelines require more trials with larger samples to establish more substantial evidence and more in-depth understanding of its roles.
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Crowley, George, Sophia Kwon, Erin J. Caraher, Syed Hissam Haider, Rachel Lam, Prag Batra, Daniel Melles, Mengling Liu, and Anna Nolan. "Quantitative lung morphology: semi-automated measurement of mean linear intercept." BMC Pulmonary Medicine 19, no. 1 (November 9, 2019). http://dx.doi.org/10.1186/s12890-019-0915-6.
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Abstract Background Quantifying morphologic changes is critical to our understanding of the pathophysiology of the lung. Mean linear intercept (MLI) measures are important in the assessment of clinically relevant pathology, such as emphysema. However, qualitative measures are prone to error and bias, while quantitative methods such as mean linear intercept (MLI) are manually time consuming. Furthermore, a fully automated, reliable method of assessment is nontrivial and resource-intensive. Methods We propose a semi-automated method to quantify MLI that does not require specialized computer knowledge and uses a free, open-source image-processor (Fiji). We tested the method with a computer-generated, idealized dataset, derived an MLI usage guide, and successfully applied this method to a murine model of particulate matter (PM) exposure. Fields of randomly placed, uniform-radius circles were analyzed. Optimal numbers of chords to assess based on MLI were found via receiver-operator-characteristic (ROC)-area under the curve (AUC) analysis. Intraclass correlation coefficient (ICC) measured reliability. Results We demonstrate high accuracy (AUCROC > 0.8 for MLIactual > 63.83 pixels) and excellent reliability (ICC = 0.9998, p < 0.0001). We provide a guide to optimize the number of chords to sample based on MLI. Processing time was 0.03 s/image. We showed elevated MLI in PM-exposed mice compared to PBS-exposed controls. We have also provided the macros that were used and have made an ImageJ plugin available free for academic research use at https://med.nyu.edu/nolanlab. Conclusions Our semi-automated method is reliable, equally fast as fully automated methods, and uses free, open-source software. Additionally, we quantified the optimal number of chords that should be measured per lung field.