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

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

  • Cell Mol Life Sci. 2024 Dec 27;82(1):30. doi: 10.1007/s00018-024-05548-x.
Min Hu # 1 2,  Xiao-Hui Guan # 1 2,  Ling-Fang Wang # 1,  Hao-Min Xu 1 2,  Shu-Fen Ke 1 2,  Qing-Yun Yuan 1,  Hui-Lan Tan 1 2,  Jie Wu 1 3,  Guan-Hui Yu 1 2,  Qi-Ming Huang 1 3,  Yu Liu 4,  Long Hu 5,  Ke-Yu Deng 1 2 3,  Hong-Bo Xin 6 7 8
Affiliations

Affiliations

  • 1 National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
  • 2 College of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
  • 3 College of Life Science, Nanchang University, Nanchang, 330031, China.
  • 4 Department of Respiratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
  • 5 Department of Pathology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
  • 6 National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China. xinhb@ncu.edu.cn.
  • 7 College of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China. xinhb@ncu.edu.cn.
  • 8 College of Life Science, Nanchang University, Nanchang, 330031, China. xinhb@ncu.edu.cn.
  • # Contributed equally.
PMID: 39725783 DOI: 10.1007/s00018-024-05548-x
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 (CD38EndKO) remarkably attenuated BLM-induced pulmonary fibrosis. In addition, CD38EndKO 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 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.

Keywords

CD38; Endothelial-to-mesenchymal transition; Inflammation; Oxidative stress; Pulmonary fibrosis.

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