Gas6-Axl signal promotes indoor VOCs exposure-induced pulmonary fibrosis via pulmonary microvascular endothelial cells–fibroblasts cross-talk

Volatile organic compounds (VOCs) as environmental pollutants were associated with respiratory diseases. Pulmonary fibrosis (PF) was characterized by an increase of extracellular matrix, leading to deterioration of lung function. The adverse effects on lung and the potential mechanism underlying VOCs induced PF had not been elucidated clearly. In this study, the indoor VOCs exposure mouse model along with an ex vivo biosensor assay was established. Based on scRNA-seq analysis, the adverse effects on lung and potential molecular mechanism were studied. Herein, the results showed that VOCs exposure from indoor decoration contributed to decreased lung function and facilitated pulmonary fibrosis in mice. Then, the whole lung cell atlas after VOCs exposure and the heterogeneity of fibroblasts were revealed. We explored the molecular interactions among various pulmonary cells, suggesting that endothelial cells contributed to fibroblasts activation in response to VOCs exposure. Mechanistically, pulmonary microvascular endothelial cells (MPVECs) secreted Gas6 after VOCs-induced PANoptosis phenotype, bound to the Axl in fibroblasts, and then activated fibroblasts. Moreover, Atf3 as the key gene negatively regulated PANoptosis phenotype to ameliorate fibrosis induced by VOCs exposure. These novel findings provided a new perspective about MPVECs could serve as the initiating factor of PF induced by VOCs exposure. Environmental Implication Indoor air pollution was considered one of the major human health concerns in modern society as people spend around 90% of their time indoors and caused 4.2 million premature deaths worldwide every year. Volatile organic compounds (VOCs) were the precursors of other typical pollutants (ozone, PM2.5 and so on) and also produced harmful secondary pollutants, which invoked in the development of deleterious effects on public health, including respiratory, circulatory system disease and so on. The present study not only underscored the process of pulmonary fibrosis induce by VOCs but also offered novel directions to mitigate its adverse effect.