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

Abstract

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 PGE2 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 PGE2 when compared with those from bleomycin-only-treated mice. Coadministration of the COX-2-selective inhibitor NS398 or the selective PGE2R EP2 inhibitor AH6809 inhibited the increase in HGF production. Inhibition of HGF signaling using PHA-665752 inhibited increases in COX-2 and PGE2. Long-term inhibition of COX-2, PGE2, or HGF reversed the reduction of TGF-β, apoptotic and MPO activities, protein levels, and hydroxyproline contents. Up-regulation of COX-2/PGE2 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.

Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2and HGF Expression via a Positive Feedback Loop

“…Collectively, our data suggest that the HGF/c-Met and COX-2/PGE 2 signaling pathways are interrelated through positive cross talk in macrophages stimulated by apoptotic cells over a 24 h period. This positive feedback loop may provide, at least in part, greater PGE 2 and HGF production in macrophages, which contribute to anti-inflammatory and antifibrotic activities induced by the interaction with apoptotic cells [12]. However, other mediators are likely involved and might participate in COX-2 and PGE 2 expression through different mechanisms since the c-Met inhibitor inhibited in part the PGE 2 as well as HGF production.…”

“…Moreover, we found that in vivo exposure to apoptotic cells induces anti-inflammatory effects through induction of COX-2/PGE 2 , and HGF signaling in bleomycin-stimulated lungs, using pharmacologic approaches [11, 12]. Our previous studies also demonstrated that in vivo exposure to apoptotic cells resulted in enhanced expression of HGF [11] and COX-2 and secretion of PGE 2 [12] until the late fibrotic phase in bleomycin-induced lung injury. These data indicate that the anti-inflammatory and antifibrotic effects in the lung following apoptotic cell instillation are correlated with coordinated increases in HGF and COX-2/PGE 2 signaling.…”

“…Recently, we demonstrated in vitro that apoptotic cell-induced HGF reduces inflammatory cytokine expression in macrophages [11]. Moreover, we found that in vivo exposure to apoptotic cells induces anti-inflammatory effects through induction of COX-2/PGE 2 , and HGF signaling in bleomycin-stimulated lungs, using pharmacologic approaches [11, 12]. Our previous studies also demonstrated that in vivo exposure to apoptotic cells resulted in enhanced expression of HGF [11] and COX-2 and secretion of PGE 2 [12] until the late fibrotic phase in bleomycin-induced lung injury.…”

Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis

“…Evidence from the literature supports a protective role for HGF in fibrotic lung disease. Apoptotic cells have been shown to modulate bleomycin lung fibrosis through the production of HGF alone [59] or in combination with PGE 2 [60]. Notably, a recent study has identified the role for a secreted factor in MSC protection against lung fibrosis and acute lung injury using conditioned medium from amniotic membrane derived cells [61] or proinflammatory cytokineactivated MSCs [62].…”

Following the Path of CCL2 from Prostaglandins to Periostin in Lung Fibrosis

“…This antifibrotic pathway also explains the beneficial effects of apoptotic cell instillation in fibrotic lungs (42). However, if true, why were wild-type mice, which had the capacity to synthesize PGE 2 and to activate plasminogen, not protected in experimental models of lung fibrosis?…”