Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis

Summary

Accumulation of senescent cells contributes to age-related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs) regulate many biological processes; however, the functional contributions of IGFBP2 in lung fibrosis remain largely unclear. Here, we report that intranasal delivery of recombinant IGFBP2 protects aged mice from weight loss and demonstrated antifibrotic effects after bleomycin lung injury. Notably, aged human- Igfbp2 transgenic mice reveal reduced senescence and senescent-associated secretory phenotype factors in alveolar epithelial type 2 (AEC2) cells and they ameliorated bleomycin-induced lung fibrosis. Finally, we demonstrate that IGFBP2 expression is significantly suppressed in AEC2 cells isolated from fibrotic lung regions of patients with IPF and/or pulmonary hypertension compared with patients with hypersensitivity pneumonitis and/or chronic obstructive pulmonary disease. Altogether, our study provides insights into how IGFBP2 regulates AEC2-cell-specific senescence and that restoring IGFBP2 levels in fibrotic lungs can prove effective for patients with IPF.

Graphical abstract

Highlights

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  IGFBP2 expression in AEC2 cells is downregulated during lung fibrosis

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  Igfbp2 deficiency increases P21, a senescence marker, following lung injury

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  Intranasal delivery of recombinant IGFBP2 protects aged mice following lung injury

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  Aged human Igfbp2 transgenic mice blunts bleomycin-induced lung fibrosis

Abstract

Chin et al. report that AEC2-cell-derived IGFBP2 inhibits P21 and negatively correlates with lung fibrosis. Using preclinical models, they reveal that AEC2-cell-derived IGFBP2 ameliorates lung fibrosis by suppressing senescence and SASP factors. Further, they show diminished IGFBP2 expression specifically in AEC2 cells of patients with IPF and IPF-PAH.