Hydrogen sulfide inhibits alveolar type II cell senescence and limits pulmonary fibrosis via promoting MDM2-mediated p53 degradation

Aim: Senescence of alveolar type II (AT2) cells is an important driver of pulmonary fibrosis. This study aimed to investigate whether and how dysregulation of hydrogen sulfide (H-2 S) production affected AT2 cell senescence, and then explored the effect of H-2 S on the communication between AT2 and fibroblasts.Methods: ICR mice were intratracheally administered with bleomycin (3 mg/kg). Sodium hydrosulfide (NaHS, 28 mu mol/kg/d) was intraperitoneally injected for 2 weeks. The H-2 S-generating enzyme cystathionine-beta-synthase (CBS) knockout heterozygous (CBS+/- ) mice were used as a low H-2 S production model.Results: Analysis of microarray datasets revealed downregulation of H-2 S-generating enzymes in lung tissues of patients with pulmonary fibrosis. Decreased H-2 S production was correlated with higher levels of cell senescence markers p53 and p21 in bleomycin-induced lung fibrosis. CBS+/- mice exhibited increased levels of p53 and p21. The numbers of AT2 cells positive for p53 and p21 were increased in CBS+/- mice as compared to control mice. H-2 S donor NaHS attenuated bleomycin-induced AT2 cell senescence both in vivo and in vitro. H-2 S donor suppressed bleomycin-induced senescence-associated secretory phenotype (SASP) of AT2 cells via inhibiting p53/p21 pathway, consequently suppressing proliferation and myofibroblast transdifferentiation of fibroblasts. Mechanically, H-2 S suppressed p53 expression by enhancing the mouse double-minute 2 homologue (MDM2)-mediated ubiquitination and degradation of p53.Conclusion: H-2 S inactivated p53-p21 pathway, consequently suppressing AT2 cell senescence as well as cell communication between senescent AT2 cells and fibroblasts. Aberrant H-2 S synthesis may contribute to the development of pulmonary fibrosis through promoting the activation loop involving senescent AT2 cells and activated fibroblasts.