CD38 Mediates Lung Fibrosis by Promoting Alveolar Epithelial Cell Aging

A prevailing paradigm recognizes idiopathic pulmonary fibrosis (IPF) originating from various alveolar epithelial cell (AEC) injuries, and there is a growing appreciation of AEC aging as a key driver of the pathogenesis. However, it is incompletely understood what main factor(s) contributes to the worsened alveolar epithelial aging in lung fibrosis. It remains a challenge how to dampen AEC aging, and thereby mitigating the disease progression.To determine the role of AEC CD38 in promoting cellular aging and lung fibrosis.scRNA-seq and animal models were used.We discovered a pivotal role of CD38, a cardinal nicotinamide adenine dinucleotide (NAD) hydrolase, in AEC aging and its promotion of lung fibrosis. We found increased CD38 expression in idiopathic pulmonary fibrosis (IPF) lungs that inversely correlated with the lung function of patients. CD38 was primarily located in the AECs of human lung parenchyma and was markedly induced in IPF AECs. Similarly, CD38 expression was elevated in the AECs of fibrotic lungs of young mice and further augmented in those of old mice, which was in accordance with worsened AEC aging phenotype and aggravated lung fibrosis in the old animals. We found that CD38 elevation downregulated intracellular NAD, which likely led to the aging promoting impairment of the NAD-dependent cellular and molecular activities. Furthermore, we demonstrated that genetic and pharmacological inactivation of CD38 improved these NAD dependent events and ameliorated bleomycin induced lung fibrosis.Our study suggests targeting alveolar CD38 as a novel and effective therapeutic strategy to treat this pathology.