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: 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.

Measurements and Main 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.