Coordinated induction of cyclooxygenase-2/prostaglandin E2 and hepatocyte growth factor by apoptotic cells prevents lung fibrosis

Apoptotic cell instillation after bleomycin induces persistent HGF production and protects from pulmonary fibrosis, but the underlying mechanism remains unclear. We investigated immediate and prolonged effects of in vivo instillation of apoptotic cells into bleomycin-stimulated mouse lungs (2 days old) on COX-2 expression in lung tissue and alveolar macrophages and PGE(2) production in BALF. Furthermore, functional interaction between these molecules and HGF, following apoptotic cell instillation in a bleomycin-induced lung fibrosis model, was assessed. Apoptotic cell instillation results in enhanced immediate and prolonged expression of COX-2 and PGE(2) when compared with those from bleomycin-only-treated mice. Coadministration of the COX-2-selective inhibitor NS398 or the selective PGE(2)R EP2 inhibitor AH6809 inhibited the increase in HGF production. Inhibition of HGF signaling using PHA-665752 inhibited increases in COX-2 and PGE(2). Longterm inhibition of COX-2, PGE(2), or HGF reversed the reduction of TGF-beta, apoptotic and MPO activities, protein levels, and hydroxyproline contents. Up-regulation of COX-2/PGE(2) and HGF through a positive-feedback loop may be an important mechanism whereby apoptotic cell instillation exerts the net results of anti-inflammatory, antiapoptotic, and antifibrotic action.