| Role of protease-activated receptor-2 in idiopathic pulmonary fibrosis. | |
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MedLine Citation:
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PMID: 21471103 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Activation of the coagulation cascade has been demonstrated in pulmonary fibrosis. In addition to its procoagulant function, various coagulation proteases exhibit cellular effects that may also contribute to fibrotic processes in the lung. OBJECTIVE: To investigate the importance of protease-activated receptor (PAR)-2 and its activators, coagulation factor VIIa (FVIIa)/tissue factor (TF), in the development of idiopathic pulmonary fibrosis (IPF). METHODS: Expression and localization of PAR-2 and its activators were examined in IPF lung tissue. The ability of PAR-2 to mediate various cellular processes was studied in vitro. MEASUREMENTS AND MAIN RESULTS: Expression of PAR-2 was strongly elevated in IPF lungs and was attributable to alveolar type II cells and fibroblasts/myofibroblasts. Transforming growth factor-β(1), a key profibrotic cytokine, considerably enhanced PAR-2 expression in human lung fibroblasts. FVIIa stimulated proliferation of human lung fibroblasts and extracellular matrix production in a PAR-2-dependent manner, but did not initiate differentiation of fibroblasts into myofibroblasts. PAR-2/FVIIa-driven mitogenic activities were mediated via the p44/42 mitogen-activated protein kinase pathway and were independent of factor Xa and thrombin production. Proproliferative properties of FVIIa were markedly potentiated in the presence of TF and abrogated by TF antisense oligonucleotides. Hyperplastic alveolar type II cells overlying fibroblastic foci were found to be the source of FVII in IPF lungs. Moreover, TF colocalized with PAR-2 on fibroblasts/myofibroblasts in IPF lungs. CONCLUSIONS: The PAR-2/TF/FVIIa axis may contribute to the development of pulmonary fibrosis; thus, interference with this pathway confers novel therapeutic potential for the treatment of IPF. |
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Authors:
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Malgorzata Wygrecka; Grazyna Kwapiszewska; Ewa Jablonska; Susanne von Gerlach; Ingrid Henneke; Dariusz Zakrzewicz; Andreas Guenther; Klaus T Preissner; Philipp Markart |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2011-03-11 |
Journal Detail:
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Title: American journal of respiratory and critical care medicine Volume: 183 ISSN: 1535-4970 ISO Abbreviation: Am. J. Respir. Crit. Care Med. Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-06-22 Completed Date: 2011-08-18 Revised Date: 2012-03-22 |
Medline Journal Info:
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Nlm Unique ID: 9421642 Medline TA: Am J Respir Crit Care Med Country: United States |
Other Details:
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Languages: eng Pagination: 1703-14 Citation Subset: AIM; IM |
Affiliation:
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Department of Biochemistry, Faculty of Medicine, University of Giessen Lung Center, Friedrichstrasse 24, 35392 Giessen, Germany. malgorzata.wygrecka@innere.med.uni-giessen.de |
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Differentiation
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physiology Factor VIIa / physiology Factor Xa / physiology Female Fibroblasts / pathology Fibronectins / biosynthesis Humans Idiopathic Pulmonary Fibrosis / etiology*, metabolism, pathology Lung / pathology Male Middle Aged Mitosis Myofibroblasts / pathology Osteopontin / biosynthesis Pulmonary Alveoli / pathology Receptor, PAR-2 / analysis, physiology* Thrombin / biosynthesis Thromboplastin / physiology Transforming Growth Factor beta / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Fibronectins; 0/Receptor, PAR-2; 0/Transforming Growth Factor beta; 106441-73-0/Osteopontin; 9035-58-9/Thromboplastin; EC 3.4.21.21/Factor VIIa; EC 3.4.21.5/Thrombin; EC 3.4.21.6/Factor Xa |
| Comments/Corrections | |
Comment In:
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Am J Respir Crit Care Med. 2012 Feb 15;185(4):458-9; author reply 459-60
[PMID:
22336682
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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