SMTP-44D, a Novel Soluble Epoxide Hydrolase Inhibitor, Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice

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Abstract Rationale: SMTP-44D is one of the Stachybotrys microspora triprenyl phenol (SMTP) homologues extracted from the filamentous fungus Stachybotrys microspora. SMTP-44D inhibits the enzymatic activity of soluble hydrolase inhibitor, which suppresses the hydrolysis of Epoxyeicosatrienoic acids (EETs). While EETs are known for their anti-fibrotic properties, the efficacy of SMTP-44D in pulmonary fibrosis has not been previously examined. This study investigated the antifibrotic effect of SMTP-44D using human lung fibroblasts and a murine model of pulmonary fibrosis. Methods: The expression of pro-fibrotic markers in lung fibroblasts was assessed using quantitative PCR. The proliferation of fibroblasts was evaluated using a 3 H-thymidine incorporation assay. Experimental pulmonary fibrosis was induced in mice by intratracheal administration of bleomycin. Mice received intraperitoneal injections of SMTP-44D three times per week. Lung tissues were harvested on day 21 for histopathological examination and collagen content analysis. Results:In vitro, both SMTP-44D and EETs reduced the expression of COL1A1 and ACTA2 induced by TGF-β1 in lung fibroblasts. Fibroblast proliferation induced by PDGF-BB and FGF2 was inhibited by SMTP-44D but not by EETs. In vivo, the result of histological and collagen assays significantly improved by SMTP-44D treatment. Conclusions: These findings suggest that SMTP-44D is a promising therapeutic candidate for the treatment of pulmonary fibrosis.

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