Prostaglandin E2 Differentially Regulates Vascular Endothelial Growth Factor And Interleukin-8 Production In Human Lung Fibroblasts

Rationale: Vascular Endothelial Growth Factor (VEGF) and Interleukin-8 (IL-8) are cytokines related to the pathogenesis of chronic obstructive pulmonary disease (COPD). Prostaglandin E (PGE ) and E-prostanoid (EP) receptors modulate many lung fibroblast functions involved in COPD. We investigated the potential involvement of autocrine PGE and EP receptors in the production of VEGF and IL-8 from human lung fibroblasts obtained from control, smokers, or COPD subjects. Methods: Lung fibroblasts from surgical specimens of Control (C) (n=6), Smoker (HS) (n=6) and COPD patients (n=8) were cultured, and basal PGE , VEGF, and IL-8 were measured in supernatants by ELISA. Cyclooxygenase (COX) 1, COX-2 and EP receptors were evaluated in cell lysate by western blot and by RT-PCR. Human fetal lung fibroblasts (HFL-1; lung, diploid, human) were stimulated with exogenous PGE or with supernatants from fibroblasts with different levels of PGE . The effects of PGE depletion by affinity sorbent and of EP2 and EP3 agonists or EP1 and EP4 antagonists were evaluated on VEGF and IL-8 release. Results: PGE , VEGF, and IL-8 levels, COX-2, EP2, and EP4 protein expression and mRNA were increased in COPD when compared to Controls. PGE positively correlated with VEGF and IL-8 levels in all groups of subjects. Synthetic PGE as well as the PGE -containing supernatants from cultured COPD fibroblasts increased the release of VEGF and IL-8 from stimulated HFL-1 but with different potency. This effect was mimicked by an EP2 agonist and modulated by an EP4 antagonist Conclusions: We found that PGE biosynthesis and activity are enhanced in lung fibroblasts from COPD patients, as a result of an increase in COX-2, EP2 and, possibly, EP4 receptor expression. PGE appeared to differentially affect the production of VEGF and of IL-8, with higher concentrations needed to steer fibroblasts toward the production of inflammatory cytokines during airway inflammation in COPD patients. As a result, while a basal production of PGE may have an homeostatic role driving the production of VEGF, the increased expression of COX-2 and of EP receptors may turn PGE into a pro-inflammatory factor in COPD subjects.