The proteasome-dependent degradation of ALKBH5 regulates ECM deposition in PM2.5 exposure-induced pulmonary fibrosis of mice.

Long-term inhalation of fine particulate matter (PM2.5) can cause serious effects on the respiratory system. It might be attributed to the fact that PM2.5 could directly enter and deposit in lung tissues. We established models of PM2.5 exposure in vivo and in vitro to explore the adverse effects of ambient PM2.5 on pulmonary and its potential pathogenic mechanisms. Our results showed that PM2.5 exposure promoted the deposition of ECM and the increased stiffness of the lungs, and then led to pulmonary fibrosis in time- and dose- dependent manners. Pulmonary function test showed restrictive ventilation function in mice after PM2.5 exposure. After PM2.5 exposure, ALKBH5 was recognized by TRIM11 and then degraded through the proteasome pathway. ALKBH5 deficiency (ALKBH5-/-) aggravated restrictive ventilatory disorder and promoted ECM deposition in lungs of mice induced by PM2.5. And the YAP1 signaling pathway was more activated in ALKBH5-/- than WT mice after PM2.5 exposure. In consequence, decreased ALKBH5 protein levels regulated miRNAs and then the miRNAs-targeted YAP1 signaling was activated to promote pulmonary fibrosis induced by PM2.5.