title: The cyclooxygenase-2-prostaglandin E2 pathway maintains senescence of chronic obstructive pulmonary disease fibroblasts.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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
  Fibroblasts were isolated from patients with COPD and from smoker and nonsmoker control subjects. Senescence markers and inflammatory mediators were investigated in fibroblasts and in mice.
  
  
  RESULTS
  Lung fibroblasts from patients with COPD exhibited higher expression of PGE2 receptors EP2 and EP4 as compared with nonsmoker and smoker control subjects. Compared with both nonsmoker and smoker control subjects, 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, IL-6, IL-8, growth-regulated oncogene (GRO), CX3CL1, and matrix metalloproteinase-2 protein and cyclooxygenase-2 and mPGES-1 mRNA expression. Using in vitro pharmacologic approaches and in vivo experiments in wild-type and p53(-/-) mice we demonstrated that PGE2 produced by senescent COPD fibroblasts is responsible for the increased senescence and related inflammation. PGE2 acts either in a paracrine or autocrine fashion by a pathway involving EP2 and EP4 prostaglandin receptors, cyclooxygenase-2-dependent reactive oxygen species production and signaling, and consecutive p53 activation.
  
  
  CONCLUSIONS
  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 a new basis to dampen senescence and senescence-associated inflammation in COPD.
authors: Faculté de Médecine, Université Paris-Est, UMR U955, Créteil, France.
authors: Maylis
authors: M
authors: Dagouassat
authors: Jean-Marie
authors: JM
authors: Gagliolo
authors: Sandra
authors: S
authors: Chrusciel
authors: Marie-Claude
authors: MC
authors: Bourin
authors: Corinne
authors: C
authors: Duprez
authors: Philippe
authors: P
authors: Caramelle
authors: Laurent
authors: L
authors: Boyer
authors: Sophie
authors: S
authors: Hue
authors: Jean-Baptiste
authors: JB
authors: Stern
authors: Pierre
authors: P
authors: Validire
authors: Dan
authors: D
authors: Longrois
authors: Xavier
authors: X
authors: Norel
authors: Jean-Luc
authors: JL
authors: Dubois-Randé
authors: Sabine
authors: S
authors: Le Gouvello
authors: Serge
authors: S
authors: Adnot
authors: Jorge
authors: J
authors: Boczkowski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication; D016022:Case-Control Studies; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D019899:Paracrine Communication; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D017382:Reactive Oxygen Species; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051546:Cyclooxygenase 2; D015232:Dinoprostone