Bml-111 Suppresses Tgf-Beta 1-Induced Lung Fibroblast Activation In Vitro And Decreases Experimental Pulmonary Fibrosis In Vivo

Pulmonary fibrosis is an aggressive end-stage disease. Transforming growth factor-beta 1 (TGF-beta 1) mediates lung fibroblast activation and is essential for the progress of pulmonary fibrosis. BML-111, a lipoxinA(4) (LXA(4)) receptor (ALX) agonist, has been reported to possess anti-fibrotic properties. The present study aimed to elucidate whether BML-111 inhibits TGF-beta 1-induced mouse embryo lung fibroblast (NIH3T3 cell line) activation in vitro and bleomycin (BLM)-induced pulmonary fibrosis in vivo. In vitro experiments demonstrated that BML-111 treatment inhibits TGF-beta 1-induced NIH3T3 cell viability and the expression of smooth muscle alpha actin (alpha-SMA), fibronectin and total collagen. Furthermore, this suppressive effect was associated with mothers against decapentaplegic homolog (Smad)2/3, extracellular signal-regulated kinase (ERK) and Akt phosphorylation interference. In vivo experiments revealed that BML-111 treatment markedly improved survival rate and ameliorated the destruction of lung tissue structure. It also reduced interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) and TGF-beta 1 expression in the BLM intratracheal mouse model. In addition, the expression of alpha-SMA and extracellular matrix (ECM) deposition (total collagen, hydroxyproline and fibronectin) were also suppressed following BML-111 treatment. However, BOC-2, an antagonist of ALX, partially weakened the effects of BML-111. In conclusion, these results indicated that BML-111 inhibits TGF-beta 1-induced fibroblasts activation and alleviates BLM-induced pulmonary fibrosis. Therefore, BML-111 may be used as a potential therapeutic agent for pulmonary fibrosis treatment.