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The COX2/PGE2 Pathway Maintains Senescence of Chronic Obstructive Pulmonary Disease Fibroblasts.
MedLine Citation:
PMID:  23328527     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Rationale. Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by the irreversible loss of replicative capacity associated with the secretion of inflammatory mediators. However, the mechanisms of this phenomenon remain poorly defined. Objectives. The aim of this study was to analyze the role of prostaglandin E2 (PGE2), a prostaglandin known to be increased in COPD lung fibroblasts, in inducing senescence and related inflammation in vitro in lung fibroblasts and in vivo in mice. Methods and main results. Lung fibroblasts from COPD patients exhibited higher expression of PGE2 receptors EP2 and EP4 as compared to non-smoker and smoker controls. Compared to both non-smoker and smoker controls, during long-term culture, COPD fibroblasts displayed increased senescent markers (increased senescence associated-β galactosidase activity, p16 and p53 expression and lower proliferative capacity), and an increased PGE2, IL6, IL8, GRO, CX3CL1 and MMP2 protein and COX2 and mPGES-1 mRNA expression. Using in vitro pharmacological approaches and in vivo experiments in wild type and p53 -/- mice we demonstrated that PGE2 produced by senescent COPD fibroblasts is responsible of the increased senescence and related inflammation. PGE2 acts either paracrinally or autocrinally via a pathway involving EP2 and EP4 prostaglandin receptors, COX2-dependent reactive oxygen species production and signaling, and consecutive p53 activation. Conclusion. PGE2 is a critical component of an amplifying and self-perpetuating circle inducing senescence and inflammation in COPD fibroblasts. Modulating the described PGE2 signaling pathway could provide new basis to dampen senescence and senescence-associated inflammation in COPD.
Authors:
Maylis Dagouassat; Jean-Marie Gagliolo; Sandra Chrusciel; Marie-Claude Bourin; Corinne Duprez; Philippe Caramelle; Laurent Boyer; Sophie Hue; Jean-Baptiste Stern; Pierre Validire; Dan Longrois; Xavier Norel; Jean-Luc Dubois-Randé; Sabine Le Gouvello; Serge Adnot; Jorge Boczkowski
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-17
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  -     ISSN:  1535-4970     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Université Paris-Est, UMR U955, Faculté de Medecine, CRETEIL, France.
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