The ZIP8/SIRT1 axis regulates alveolar progenitor cell renewal in aging and idiopathic pulmonary fibrosis

Type 2 alveolar epithelial cells (AEC2s) function as progenitor cells in the lung. We have shown previously that failure of AEC2 regeneration results in progressive lung fibrosis in mice and is a cardinal feature of idiopathic pulmonary fibrosis (IPF). In this study, we identified deficiency of a specific zinc transporter, SLC39A8 (ZIP8), in AEC2s from both IPF lungs and lungs of old mice. Loss of ZIP8 expression was associated with impaired renewal capacity of AEC2s and enhanced lung fibrosis. ZIP8 regulation of AEC2 progenitor function was dependent on SIRT1. Replenishment with exogenous zinc and SIRT1 activation promoted self-renewal and differentiation of AEC2s from lung tissues of IPF patients and old mice. Deletion of Zip8 in AEC2s in mice resulted in impaired AEC2 renewal, increased susceptibility to bleomycin injury, and development of spontaneous lung fibrosis. Therapeutic strategies to restore zinc metabolism and appropriate SIRT1 signaling could improve AEC2 progenitor function and mitigate ongoing fibrogenesis.

Automated summary

This study identified a deficiency of the zinc transporter SLC39A8 (ZIP8) in Type 2 alveolar epithelial cells (AEC2s) from both idiopathic pulmonary fibrosis (IPF) lungs and lungs of old mice, which is associated with impaired AEC2 renewal capacity and enhanced lung fibrosis. The regulation of AEC2 progenitor function by ZIP8 is dependent on SIRT1. Replenishment with exogenous zinc and activation of SIRT1 promote self-renewal and differentiation of AEC2s, and therapeutic strategies targeting zinc metabolism and SIRT1 signaling could potentially improve AEC2 progenitor function and mitigate fibrogenesis.