Endothelial CD38-induced endothelial-to-mesenchymal transition is a pivotal driver in pulmonary fibrosis
Min Hu, Xiao‐Hui Guan, Lingfang Wang, Huan Xu, KeWei Song, Qingyun Yuan, Hui-Lan Tan, Jie Wu, Guan-Hui Yu, Qiming Huang, Yu Liu, Long Hu, Ke‐Yu Deng, Hong‐Bo Xin
Abstract
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 (CD38 EndKO ) remarkably attenuated BLM-induced pulmonary fibrosis. In addition, CD38 EndKO significantly inhibited TGFβ-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 HUVECs CD38KD cells and 78 C, a CD38-specific inhibitor, on BLM-induced EndMT in HUVECs. Therefore, we concluded that CD38 EndKO 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. Protective role and the underlying mechanism of endothelial CD38 in bleomycin-induced pulmonary fibrosis in mice. Endothelial cells-specific CD38 knockout (CD38 EndKO ) inhibited TGFβ-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