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Wang, Xiu-Li; Xu, Yi-Tong; Zhang, Shu-Li; Zhu, Xiao-Yan; Zhang, Hong-Xia; Liu, Yu-Jian
Acta physiologica (Oxford, England) 240, Issue: 1Journal Article
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 S) production affected AT2 cell senescence, and then explored the effect of H S on the communication between AT2 and fibroblasts. ICR mice were intratracheally administered with bleomycin (3 mg/kg). Sodium hydrosulfide (NaHS, 28 μmol/kg/d) was intraperitoneally injected for 2 weeks. The H S-generating enzyme cystathionine-β-synthase (CBS) knockout heterozygous (CBS ) mice were used as a low H S production model. Analysis of microarray datasets revealed downregulation of H S-generating enzymes in lung tissues of patients with pulmonary fibrosis. Decreased H 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 S donor NaHS attenuated bleomycin-induced AT2 cell senescence both in vivo and in vitro. H 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 S suppressed p53 expression by enhancing the mouse double-minute 2 homologue (MDM2)-mediated ubiquitination and degradation of p53. H S inactivated p53-p21 pathway, consequently suppressing AT2 cell senescence as well as cell communication between senescent AT2 cells and fibroblasts. Aberrant H S synthesis may contribute to the development of pulmonary fibrosis through promoting the activation loop involving senescent AT2 cells and activated fibroblasts.
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