Chronic Obstructive Pulmonary Disease

Cosio, Manuel G.; Guerassimov, Alexei

doi:10.1164/ajrccm.160.supplement_1.7

Cited by 131 publications

(36 citation statements)

References 17 publications

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“…Three major consequences of cigarette smoke-induced lung injury are chronic mucus hypersecretion, airway inflammation and narrowing, and destruction of alveolar septi (31)(32)(33)(34)(35). It has been shown that mitogen-activated protein kinase activation alters mucin production and inflammation in the lung (36).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

158

172

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The interstitial collagenase matrix metalloproteinase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERKdependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.

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Section: Discussionmentioning

confidence: 99%

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

158

172

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“…This can be appreciated in the joint erosions in rheumatoid arthritis, ulcerations in Behçet's and apthous lesions, gingival atrophy in periodontal disease, gastric atrophy in autoimmune gastritis, ocular destruction in uveoritinitis, and histologic necrosis in mycobacterial granulomas (6 -12). This is also seen in pulmonary emphysema where alveolar septal rupture and enhanced type I cytokine production, increased numbers of CD3 ϩ and CD8 ϩ cells that produce IFN-␥, and increased levels of the IFN-␥ target gene IFN-␥-inducible protein 10/CXCL10 are juxtaposed (13)(14)(15)(16)(17)(18). Studies from our laboratory have also demonstrated that the transgenic overexpression of IFN-␥ in the adult murine lung causes pulmonary emphysema (19).…”

mentioning

confidence: 89%

Role of Cathepsin S-Dependent Epithelial Cell Apoptosis in IFN-γ-Induced Alveolar Remodeling and Pulmonary Emphysema

Zheng

Kang

Crothers

et al. 2005

The Journal of Immunology

128

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Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-γ, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-γ-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-γ uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-γ caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethyl-ketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN-γ-induced emphysema. These interventions also ameliorated IFN-γ-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-γ-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN-γ-induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.

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“…These responses are readily apparent in chronic obstructive pulmonary disease (COPD), 3 which is characterized by inflammation with increased numbers of CD8 ϩ lymphocytes, macrophages, eosinophils, and granulocytes (1)(2)(3)(4), and a remodeling response that causes the alveolar septal destruction and changes in compliance that are characteristic of pulmonary emphysema (1). Asthma is characterized by chronic tissue inflammation with increased numbers of eosinophils, macrophages, and lymphocytes, which are believed to cause the subepithelial fibrosis, mucus metaplasia, and myocyte hyperplasia that are prominent features of the remodeled asthmatic airway (5,6).…”

Section: Il-13-induced Chemokine Responses In the Lung: Role Of Ccr2 mentioning

confidence: 99%

IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

Zhu¹,

Ma²,

Zheng³

et al. 2002

The Journal of Immunology

180

159

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IL-13 stimulates inflammatory and remodeling responses and contributes to the pathogenesis of human airways disorders. To further understand the cellular and molecular events that mediate these responses, we characterized the effects of IL-13 on monocyte chemotactic proteins (MCPs) and compared the tissue effects of transgenic IL-13 in mice with wild-type (+/+) and null (−/−) CCR2 loci. Transgenic IL-13 was a potent stimulator of MCP-1, -2, -3, and -5. This stimulation was not specific for MCPs because macrophage-inflammatory protein (MIP)-1α, MIP-1β, MIP-2, MIP-3α, thymus- and activation-regulated chemokine, thymus-expressed chemokine, eotaxin, eotaxin 2, macrophage-derived chemokines, and C10 were also induced. The ability of IL-13 to increase lung size, alveolar size, and lung compliance, to stimulate pulmonary inflammation, hyaluronic acid accumulation, and tissue fibrosis, and to cause respiratory failure and death were markedly decreased, whereas mucus metaplasia was not altered in CCR2−/− mice. CCR2 deficiency did not decrease the basal or IL-13-stimulated expression of target matrix metalloproteinases or cathepsins but did increase the levels of mRNA encoding α1-antitrypsin, tissue inhibitor of metalloproteinase-1, -2, and -4, and secretory leukocyte proteinase inhibitor. In addition, the levels of bioactive and total TGF-β1 were decreased in lavage fluids from IL-13 transgenic mice with −/− CCR2 loci. These studies demonstrate that IL-13 is a potent stimulator of MCPs and other CC chemokines and document the importance of MCP-CCR2 signaling in the pathogenesis of the IL-13-induced pulmonary phenotype.

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Chronic Obstructive Pulmonary Disease

Cited by 131 publications

References 17 publications

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Role of Cathepsin S-Dependent Epithelial Cell Apoptosis in IFN-γ-Induced Alveolar Remodeling and Pulmonary Emphysema

IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

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