Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease and eventually, most of patients were subjected to respiratory failure with a median survival of 2 to 3 years after diagnosis due to a lack of effective therapies in clinic. Mogroside IIIE (MGIIIE), a cucurbitane-type compound, was isolated from Siraitia grosvenorii. MGIIIE has shown strongest inhibition of NO release, a crucial inflammatory factor, from LPS-treated RAW264.7 cells compared with other mogrosides. In pulmonary fibrosis mouse model induced by bleomycin, MGIIIE treatment attenuated pulmonary fibrosis indicated as a reduction in myeloperoxidase (MPO) activity, collagen deposition as well as pathological score. Second, MGIIIE significantly suppressed expression of several important fibrotic markers e.g. α-SMA, collagen I, TGF-β signal and MMP-9/TIMP-1. Furthermore, MGIIIE blocked tansdifferentiation of lung resident fibroblasts into myofibroblast-like cells induced by TGF-β or LPS and subsequently inhibited collagen production in lung fibroblasts. These data indicate that MGIIIE is a potent inhibitor for pulmonary fibrosis. In vitro and in vivo mechanistic studies have shown that MGIIIE significantly decreased expression of TLR4 and its downstream signals MyD88-MAPK, an inflammatory signal essential for extracellular matrix (ECM) deposition in pulmonary fibroblasts. Taken together, these results demonstrate that MGIIIE significantly prevents pulmonary fibrosis by inhibiting pulmonary inflammation and ECM deposition through regulating TLR4/MyD88-MAPK signaling. Our study suggests that MGIIIE may have therapeutic potential for treating pulmonary fibrosis in clinic settings.
- The American Society for Pharmacology and Experimental Therapeutics