Previous our study reported that instillation of apoptotic cells after bleomycin induces persistent HGF production and protects from fibrosis, but the mechanism underlying this antifibrotic effect remains unclear. In the present study, we investigated immediate and prolonged effects of apoptotic cell instillation on the potent antifibrotic molecules, such as COX-2/PGE2. Furthermore, we characterized the functional interaction between these molecules and HGF upon in vivo exposure to apoptotic cells in the injured lung processing extensive fibrosis, using selective inhibitors of these molecules. Apoptotic cell instillation after bleomycin results in further enhancement of immediate and prolonged expression of COX-2 in lung and alveolar macrophages compared with those of bleomycin only treated mice. Coadministration at the same time with apoptotic cells and sequential administration of the COX-2 selective inhibitor, NS-398, the selective PGE2 receptor EP2 inhibitor, AH6809, reversed the increases in immediate and prolonged mRNA and protein expression of HGF in lung and alveolar macrophages. On the other hand, inhibition of HGF signaling using the c-Met antagonist PHA-665752 reversed the immediate and prolonged increases in COX-2 mRNA and protein expression as well as PGE2 production in lung and alveolar macrophages following apoptotic cell instillation. In functional relevance, these inhibitors, including NS-398, AH6809, and PHA-665752, reversed the reduction of hydroxyproline content, as well as proapoptotic activity of caspase-3 and -9 and MPO activity following apoptotic cell instillation. These findings indicate that interaction with apoptotic cells in vivo induces persistent upregulation of COX-2/PGE2 and HGF in a positive feedback loop. The greater and prolonged production of these molecules may be an important mechanism whereby apoptotic cell instillation exerts the net results of anti-inflammatory, anti-apoptotic and anti-fibrotic action.