Targeting acid sphingomyelinase/ceramide/S1P ameliorates silica-induced pulmonary fibrosis through Hippo/YAP signaling pathway in mice

Silicosis is irreversible lung disease caused by exposure to dust-containing silica particles. Our study aims to explore the potential effects of acid sphingomyelinase (aSMase), ceramide (Cer) and sphingosine-1-phosphate (S1P) on silica-induced pulmonary fibrosis. We also explored the expression of the downstream signaling pathway of Hippo/YAP. The high expression of SMPD1 which encodes aSMase were given. The level of aSMase in silicosis was lower than those in controls. Additionally, the level of aSMase in lung fibroblasts, following stimulation with TGF-β1, was observed to decrease. The phagocytosis of silica particles by macrophages promoted lung fibroblast transdifferentiation and activated the aSMase/Cer/S1P signaling pathway. The activated Hippo/YAP signaling pathway is involved in silica-induced pulmonary fibrosis. Moreover, the collagen content within silicotic nodules and the number of large nodules were reduced by the intervention with the high expression of SMPD1 in vivo. Furthermore, the levels of fibrotic genes in TGF-β1-induced lung fibroblasts activation were diminished with the overexpression of SMPD1. ASMase was downregulated in silica-induced lung fibrosis, however the administration of exogenous SMPD1 overexpression has the potential to alleviate this condition. This process may be related to the downstream Hippo/YAP signaling pathway.