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IL-17RA Is Required for CCL2 Expression, Macrophage Recruitment, and Emphysema in Response to Cigarette Smoke  [PDF]
Kong Chen, Derek A. Pociask, Jeremy P. McAleer, Yvonne R. Chan, John F. Alcorn, James L. Kreindler, Matthew R. Keyser, Steven D. Shapiro, A. McGarry Houghton, Jay K. Kolls, Mingquan Zheng
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0020333
Abstract: Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA?/? mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA?/? mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema.
The role of collagenase in emphysema
Robert Foronjy, Jeanine D'Armiento
Respiratory Research , 2001, DOI: 10.1186/rr85
Abstract: Emphysema is a common, debilitating pulmonary condition, the impact of which is felt worldwide, placing an enormous economic strain on international health care infrastructures. In the UK, data from 1996 indicate that the medical cost of chronic obstructive pulmonary disease (COPD) was approximately £846 million or about £1154 per person per year [1]. In the USA, over 106,000 people die from COPD yearly making it the fourth leading cause of death nationwide [2]. Moreover, while death rates for heart disease and stroke have declined by roughly 50% over the past 30 years, the death rate for COPD has risen by 71% [2]. In 1993, it was estimated that 14.7 billion dollars were spent in the USA on direct COPD-related health care expenditures, costing roughly the equivalent of £764 per person per year [1]. As the life expectancy of the populations of industrialized nations continues to increase, it is certain that the costs of emphysema in terms of lives lost and strains on limited health care resources will continue to grow.In light of these statistics on the global impact of this disease, it is surprising to realize that even the basic pathophysiology of emphysema is still being debated. While it is clearly established that cigarette smoke is the principal cause of emphysema, the mechanism by which cigarette smoke exposure leads to the destruction of lung architecture seen in emphysema is controversial. Elastin is an important component of the extracellular matrix (ECM) that is believed to confer upon the lung the resilience needed to undergo repetitive physiologic stress. For over 30 years, the leading hypothesis has been that emphysema resulted from an elastase/anti-elastase imbalance. This theory was formulated after it was noted that smokers with a congenital deficiency of alpha-1-antitrypsin (a1-AT) had an excessive incidence of emphysema [3]. Given the increased neutrophil content seen in the lungs of smokers and the fact that a1-AT inactivates neutrophil elastase,
Inflammatory changes in the airways of mice caused by cigarette smoke exposure are only partially reversed after smoking cessation
Saskia Braber, Paul AJ Henricks, Frans P Nijkamp, Aletta D Kraneveld, Gert Folkerts
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-99
Abstract: The severity of airway remodeling and inflammation was studied by analyzing alveolar enlargement, heart hypertrophy, inflammatory cells in the bronchoalveolar lavage fluid (BALF) and lung tissue and by determining the cytokine and chemokine profiles in the BALF of A/J mice exposed to cigarette smoke for 20 weeks and 8 weeks after smoking cessation.The alveolar enlargement and right ventricle heart hypertrophy found in smoke-exposed mice remained unchanged after smoking cessation. Although the neutrophilic inflammation in the BALF of cigarette smoke-exposed animals was reduced after smoking cessation, a sustained inflammation in the lung tissue was observed. The elevated cytokine (IL-1α and TNF-α) and chemokine (CCL2 and CCL3) levels in the BALF of smoke-exposed mice returned to basal levels after smoking cessation, while the increased IL-12 levels did not return to its basal level. The cigarette smoke-enhanced VEGF levels did not significantly change after smoking cessation. Moreover, IL-10 levels were reduced in the BALF of smoke-exposed mice and these levels were still significantly decreased after smoking cessation compared to the control animals.The inflammatory changes in the airways caused by cigarette smoke exposure were only partially reversed after smoking cessation. Although smoking cessation should be the first step in reducing the progression of lung emphysema, additional medication could be provided to tackle the sustained airway inflammation.There are currently more than 1.3 billion tobacco smokers worldwide according to the World Health Organization (WHO) [1]. Cigarette smoke contains more than 4000 hazardous chemical compounds, of which 200 are highly toxic [2]. It is generally accepted that cigarette smoking is the most important risk factor for the development and progression of chronic obstructive pulmonary disease (COPD) and accounts for about 80% of COPD cases [3,4]. COPD, a term referring to two lung diseases: chronic bronchitis and emphysema,
Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process
Geraghty P, Wallace A, D'Armiento J
International Journal of Chronic Obstructive Pulmonary Disease , 2011, DOI: http://dx.doi.org/10.2147/COPD.S19599
Abstract: duction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process Original Research (3763) Total Article Views Authors: Geraghty P, Wallace A, D'Armiento J Published Date June 2011 Volume 2011:6 Pages 309 - 319 DOI: http://dx.doi.org/10.2147/COPD.S19599 Patrick Geraghty, Alison Wallace, Jeanine M D'Armiento Department of Medicine, Divisions of Molecular and Pulmonary Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA Purpose: Cigarette smoke is the major risk factor associated with the development of chronic obstructive pulmonary disease (COPD). Recent studies propose a link between endoplasmic reticulum (ER) stress and emphysema, demonstrated by increased ER stress markers under smoking conditions. Here, we investigate whether cigarette smoke-induced ER stress is cell specific and correlates with acute and chronic cigarette smoke exposure. Methods: Gene and protein expression changes in human primary lung cell cultures following cigarette smoke extract (CSE) exposure were monitored by qPCR and Western blot analysis. Mice and guinea pigs were exposed to cigarette smoke and ER stress markers examined in whole lung homogenates. Inflammatory cells from the bronchoalveolar lavage fluid of 10 days smoke exposed mice were also examined. Results: Cigarette smoke induced a trend increase in the ER stress response through an activating transcription factor 4 (ATF4) mediated induction of C/EBP homologous protein (CHOP) in primary small airway epithelial cells. Bronchial epithelial cells and macrophages responded similarly to CSE. Wild-type mice and guinea pigs exposed to acute levels of cigarette smoke exhibited increased levels of CHOP but not at significant levels. However, after long-term chronic cigarette smoke exposure, CHOP expression was reduced. Interestingly, inflammatory cells from smoke exposed mice had a significant increase in CHOP/ATF4 expression. Conclusion: A trend increase in CHOP levels appear in multiple human lung cell types following acute cigarette smoke exposure in vitro. In vivo, inflammatory cells, predominately macrophages, demonstrate significant cigarette smoke-induced ER stress. Early induction of CHOP in cigarette smoke may play a pivotal role in early induction of lung disease, however in vivo long-term cigarette smoke exposure exhibited a reduction in the ER stress response.
Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process  [cached]
Geraghty P,Wallace A,D'Armiento J
International Journal of COPD , 2011,
Abstract: Patrick Geraghty, Alison Wallace, Jeanine M D'ArmientoDepartment of Medicine, Divisions of Molecular and Pulmonary Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USAPurpose: Cigarette smoke is the major risk factor associated with the development of chronic obstructive pulmonary disease (COPD). Recent studies propose a link between endoplasmic reticulum (ER) stress and emphysema, demonstrated by increased ER stress markers under smoking conditions. Here, we investigate whether cigarette smoke-induced ER stress is cell specific and correlates with acute and chronic cigarette smoke exposure.Methods: Gene and protein expression changes in human primary lung cell cultures following cigarette smoke extract (CSE) exposure were monitored by qPCR and Western blot analysis. Mice and guinea pigs were exposed to cigarette smoke and ER stress markers examined in whole lung homogenates. Inflammatory cells from the bronchoalveolar lavage fluid of 10 days smoke exposed mice were also examined.Results: Cigarette smoke induced a trend increase in the ER stress response through an activating transcription factor 4 (ATF4) mediated induction of C/EBP homologous protein (CHOP) in primary small airway epithelial cells. Bronchial epithelial cells and macrophages responded similarly to CSE. Wild-type mice and guinea pigs exposed to acute levels of cigarette smoke exhibited increased levels of CHOP but not at significant levels. However, after long-term chronic cigarette smoke exposure, CHOP expression was reduced. Interestingly, inflammatory cells from smoke exposed mice had a significant increase in CHOP/ATF4 expression.Conclusion: A trend increase in CHOP levels appear in multiple human lung cell types following acute cigarette smoke exposure in vitro. In vivo, inflammatory cells, predominately macrophages, demonstrate significant cigarette smoke-induced ER stress. Early induction of CHOP in cigarette smoke may play a pivotal role in early induction of lung disease, however in vivo long-term cigarette smoke exposure exhibited a reduction in the ER stress response.Keywords: COPD, ER stress, cigarette smoke, CHOP
Cigarette smoke induces β2-integrin-dependent neutrophil migration across human endothelium
Saskia A Overbeek, Saskia Braber, Paul A J Henricks, Marije Kleinjan, Vera M Kamp, Niki A Georgiou, Johan Garssen, Aletta D Kraneveld, Gert Folkerts
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-75
Abstract: Utilizing freshly isolated human PMNs, the effect of cigarette smoke on migration and β2-integrin activation and function in neutrophilic transmigration was studied. In this report, we demonstrated that cigarette smoke extract (CSE) dose dependently induced migration of neutrophils in vitro. Moreover, CSE promoted neutrophil adherence to fibrinogen. Using functional blocking antibodies against CD11b and CD18, it was demonstrated that Mac-1 (CD11b/CD18) is responsible for the cigarette smoke-induced firm adhesion of neutrophils to fibrinogen. Furthermore, neutrophils transmigrated through endothelium by cigarette smoke due to the activation of β2-integrins, since pre-incubation of neutrophils with functional blocking antibodies against CD11b and CD18 attenuated this transmigration.This is the first study to describe that cigarette smoke extract induces a direct migratory effect on neutrophils and that CSE is an activator of β2-integrins on the cell surface. Blocking this activation of β2-integrins might be an important target in cigarette smoke induced neutrophilic diseases.Neutrophils play a pivotal role in pulmonary inflammatory diseases, such as chronic obstructive pulmonary disease (COPD). COPD is a progressive disease, which is characterized by two major pathological processes, namely bronchitis and emphysema. The neutrophils accumulate in the affected tissues and contribute to the chronic inflammatory reaction, eventually leading to lung destruction [1,2]. It is generally accepted that cigarette smoking is the most important risk factor for the development of COPD. The WHO estimated that 73% of COPD mortality is related to smoking [3]. However, not only COPD patients have increased neutrophil counts in bronchoalveolar lavage fluid (BALF) and sputum [4-7]; increased neutrophil numbers are also observed in sputum of smokers without respiratory problems [5,8].To migrate from the blood stream to the lung, neutrophils use a specific set of adhesion and chemokine rec
Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema
Ingel K Demedts, Tine Demoor, Ken R Bracke, Guy F Joos, Guy G Brusselle
Respiratory Research , 2006, DOI: 10.1186/1465-9921-7-53
Abstract: In this review, recent data on the role of apoptosis in COPD from both animal models as well as from studies on human subjects will be discussed. The aim is to provide an up to date summary on the increasing knowledge on the role of apoptosis in COPD and pulmonary emphysema.Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disease that is associated with an abnormal inflammatory response of the lungs to noxious particles or gases (mainly cigarette smoke). This leads to chronic bronchitis-bronchiolitis (small airways disease) and/or emphysema that cause airflow limitation that is not fully reversible. [1]. COPD is the fifth leading cause of death worldwide, accounting for more than 2 500 000 deaths every year (WHO world health report 2002). Moreover, the prevalence and mortality of COPD are expected to increase in the coming decades [2].Several mechanisms contribute to the pathogenesis of COPD [3]. First, the inhalation of noxious particles such as cigarette smoke causes the influx of inflammatory cells into the airways and lungs, leading to chronic inflammation. Different kinds of inflammatory cells (macrophages, neutrophils, CD8+ T lymphocytes) have been described to participate in the inflammatory response in the airways of COPD patients.Second, there is a disruption of the balance between proteolytic and anti-proteolytic molecules in the lungs of COPD patients, resulting in an increased proteolytic activity [4]. This causes the destruction of healthy lung parenchyma, which leads to the development of emphysema. This increase in proteolytic activity may be a consequence of inflammation (release of proteolytic enzymes by inflammatory cells such as macrophages and neutrophils) or may arise from genetic factors (eg alpha-1 antitrypsin deficiency).A third mechanism involved in the pathogenesis of COPD is oxidative stress, which occurs when reactive oxygen species are produced in excess of the antioxidant defence mechanisms [3]. Oxidants are generat
Effect of roflumilast on inflammatory cells in the lungs of cigarette smoke-exposed mice
Piero A Martorana, Benedetta Lunghi, Monica Lucattelli, Giovanna De Cunto, Rolf Beume, Giuseppe Lungarella
BMC Pulmonary Medicine , 2008, DOI: 10.1186/1471-2466-8-17
Abstract: Slides were obtained from blocks of the previous study and VV was assessed immunohistochemically and by point counting using a grid with 48 points, a 20× objective and a computer screen for a final magnification of 580×. Neutrophils were marked with myeloperoxidase antibody, macrophages with Mac-3, dendritic cells with fascin, B-lymphocytes with B220, CD4+ T-cells with CD4+ antibody, and CD8+T-cells with CD8-α. The significance of the differences was calculated using one-way analysis of variance.Chronic smoke exposure increased neutrophil VV by 97%, macrophage by 107%, dendritic cell by 217%, B-lymphocyte by 436%, CD4+ by 524%, and CD8+ by 417%. The higher dose of roflumilast prevented the increase in neutrophil VV by 78%, macrophage by 82%, dendritic cell by 48%, B-lymphocyte by 100%, CD4+ by 98% and CD8+ VV by 88%. The lower dose of roflumilast did not prevent the increase in neutrophil, macrophage and B-cell VV but prevented dendritic cells by 42%, CD4+ by 55%, and CD8+ by 91%.These results indicate (i) chronic exposure to cigarette smoke in mice results in a significant recruitment into the lung of inflammatory cells of both the innate and adaptive immune system; (ii) roflumilast at the higher dose exerts a protective effect against the recruitment of all these cells and at the lower dose against the recruitment of dendritic cells and T-lymphocytes; (iii) these findings underline the role of innate immunity in the development of pulmonary emphysema and (iiii) support previous results indicating that the inflammatory cells of the adaptive immune system do not play a central role in the development of cigarette smoke induced emphysema in mice.Recently, chronic obstructive pulmonary disease (COPD) has been defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as a disease characterized by progressive, not fully reversible, flow limitation and "associated with an abnormal inflammatory response of the lungs to noxious particles and gases" [1].
Persistence of Th17/Tc17 Cell Expression upon Smoking Cessation in Mice with Cigarette Smoke-Induced Emphysema  [PDF]
Min-Chao Duan,Hai-Juan Tang,Xiao-Ning Zhong,Ying Huang
Journal of Immunology Research , 2013, DOI: 10.1155/2013/350727
Abstract: Th17 and Tc17 cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), a disease caused predominantly by cigarette smoking. Smoking cessation is the only intervention in the management of COPD. However, even after cessation, the airway inflammation may be present. In the current study, mice were exposed to room air or cigarette smoke for 24 weeks or 24 weeks followed by 12 weeks of cessation. Morphological changes were evaluated by mean linear intercepts (Lm) and destructive index (DI). The frequencies of CD8+IL-17+(Tc17) and CD4+IL-17+(Th17) cells, the mRNA levels of ROR gamma and IL-17, and the levels of IL-8, TNF-alpha, and IFN-gamma in lungs or bronchoalveolar lavage fluid of mice were assayed. Here we demonstrated that alveolar enlargement and destruction induced by cigarette smoke exposure were irreversible and that cigarette smokeenhanced these T-cell subsets, and related cytokines were not significantly reduced after smoking cessation. In addition, the frequencies of Th17 and Tc17 cells in lungs of smoke-exposed mice and cessation mice were positively correlated with emphysematous lesions. More important, the frequencies of Tc17 cells were much higher than Th17 cells, and there was a significantly positive correlation between Th17 and Tc17. These results suggested that Th17/Tc17 infiltration in lungs may play a critical role in sustaining lung inflammation in emphysema. Blocking the abnormally increased numbers of Tc17 and Th17 cells may be a reasonable therapeutic strategy for emphysema. 1. Introduction Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation due to airway obstruction and emphysematous destruction [1]. Smoking is the most important etiological factor in the development of airway inflammation in COPD [1]. Until now, smoking cessation is regarded as the most important intervention in reducing the progression of COPD [2]. However, in those who develop COPD this inflammatory response persists after smoking cessation, suggesting an abnormal regulation mechanism similar to those occurring in autoimmune disorders. COPD shares some features with autoimmune diseases [3–5]. Th1/Tc1 cells contribute principally, but not exclusively, to the pathogenesis of COPD. Th17 cells are now defined as a separate T-cell subset distinct from the Th1 and Th2 cells, with the expression of distinctive transcription factor ROR-ct (RAR-related orphan nuclear receptor ct in mice; RORC, RAR-related orphan nuclear receptor C in humans). IL-17A, IL-17F, IL-21, and IL-22 are secreted by and
Egr-1 Regulates Autophagy in Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease  [PDF]
Zhi-Hua Chen, Hong Pyo Kim, Frank C. Sciurba, Seon-Jin Lee, Carol Feghali-Bostwick, Donna B. Stolz, Rajiv Dhir, Rodney J. Landreneau, Mathew J. Schuchert, Samuel A. Yousem, Kiichi Nakahira, Joseph M. Pilewski, Janet S. Lee, Yingze Zhang, Stefan W. Ryter, Augustine M. K. Choi
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003316
Abstract: Background Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear. Methodology and Principal Findings Increased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3B, LC3B, Atg4, Atg5/12, Atg7). Cigarette smoke extract (CSE) is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC) inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1) and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1?/? mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema. Conclusions We demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury.
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