Endothelial CD38-induced endothelial-to-mesenchymal transition is a pivotal driver in pulmonary fibrosis

被引：0

作者：

Hu, Min ^{[1
,2
]}

Guan, Xiao-Hui ^{[1
,2
]}

Wang, Ling-Fang ^{[1
]}

Xu, Hao-Min ^{[1
,2
]}

Ke, Shu-Fen ^{[1
,2
]}

Yuan, Qing-Yun ^{[1
]}

Tan, Hui-Lan ^{[1
,2
]}

Wu, Jie ^{[1
,3
]}

Yu, Guan-Hui ^{[1
,2
]}

Huang, Qi-Ming ^{[1
,3
]}

Liu, Yu ^{[4
]}

Hu, Long ^{[5
]}

Deng, Ke-Yu ^{[1
,2
,3
]}

Xin, Hong-Bo ^{[1
,2
,3
]}

机构：

[1] Nanchang Univ, Inst Translat Med, Jiangxi Med Coll, Natl Engn Res Ctr Bioengn Drugs & Technol, Nanchang 330031, Peoples R China

[2] Nanchang Univ, Jiangxi Med Coll, Coll Pharm, Nanchang 330031, Peoples R China

[3] Nanchang Univ, Coll Life Sci, Nanchang 330031, Peoples R China

[4] Nanchang Univ, Affiliated Hosp 1, Jiangxi Med Coll, Dept Resp, Nanchang 330006, Peoples R China

[5] Nanchang Univ, Affiliated Hosp 1, Jiangxi Med Coll, Dept Pathol, Nanchang 330006, Peoples R China

来源：

CELLULAR AND MOLECULAR LIFE SCIENCES | 2024年 / 82卷 / 01期

基金：

中国国家自然科学基金;

关键词：

Pulmonary fibrosis; CD38; Endothelial-to-mesenchymal transition; Inflammation; Oxidative stress; OXIDATIVE STRESS; DISTURBED FLOW; TGF-BETA; PATHOGENESIS; DIFFERENTIATION; INFLAMMATION; FIBROBLASTS; APOPTOSIS; PATHWAYS; KINASE;

D O I：

10.1007/s00018-024-05548-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Idiopathic pulmonary fibrosis (IPF) is a prevalent interstitial lung disease with high mortality. CD38 is a main enzyme for intracellular nicotinamide adenine dinucleotide (NAD+) degradation in mammals. It has been reported that CD38 participated in pulmonary fibrosis through promoting alveolar epithelial cells senescence. However, the roles of endothelial CD38 in pulmonary fibrosis remain unknown. In the present study, we observed that the elevated expression of CD38 was related to endothelial-to-mesenchymal transition (EndMT) of lung tissues in IPF patients and bleomycin (BLM)-induced pulmonary fibrosis mice and also in human umbilical vein endothelial cells (HUVECs) treated with BLM. Micro-computed tomography (MCT) and histopathological staining showed that endothelial cell-specific CD38 knockout (CD38EndKO) remarkably attenuated BLM-induced pulmonary fibrosis. In addition, CD38EndKO significantly inhibited TGF beta-Smad3 pathway-mediated excessive extracellular matrix (ECM), reduced Toll-like receptor4-Myeloid differentiation factor88-Mitogen-activated protein kinases (TLR4-MyD88-MAPK) pathway-mediated endothelial inflammation and suppressed nicotinamide adenine dinucleotide phosphate oxidases1 (NOX1)-mediated oxidative stress. Furthermore, we demonstrated that 3-TYP, a SIRT3-specific inhibitor, markedly reversed the protective effect of HUVECsCD38KD cells and 78 C, a CD38-specific inhibitor, on BLM-induced EndMT in HUVECs. Therefore, we concluded that CD38EndKO significantly ameliorated BLM-induced pulmonary fibrosis through inhibiting ECM, endothelial inflammation and oxidative stress, further alleviating EndMT in mice. Our findings suggest that endothelial CD38 may be a new therapeutic target for the prevention and treatment of pulmonary fibrosis clinically.Graphical Abstract Protective role and the underlying mechanism of endothelial CD38 in bleomycin-induced pulmonary fibrosis in mice. Endothelial cells-specific CD38 knockout (CD38EndKO) inhibited TGF beta-Smad3-mediated ECM, ROS-mediated oxidative stress and TLR4-mediated inflammation, and in turn, suppressed endothelial-to-mesenchymal transition (EndMT), eventually, alleviated pulmonary fibrosis induced by bleomycin in mice, suggesting endothelial CD38 may be a therapeutic target for the prevention and the treatment of pulmonary fibrosis clinically

引用

页数：21

共 61 条

[1] NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFβ1-induced fibroblast differentiation into myofibroblasts [J].