A new study has shown that insulin-like growth factor binding protein (IGFBP) levels are significantly reduced in fibrotic lungs, and their restoration might improve fibrosis in patients with idiopathic pulmonary fibrosis (IPF).
The study, published in Cell Reports Medicine, employed intranasal delivery of recombinant IGFBP2 proteins in a mouse model of IPF.
“In the current study, we investigated whether IGFBP2 regulates cellular senescence and secretion of senescent factors specifically in [alveolar epithelial type 2 (AEC2)] cells in the development of pulmonary fibrosis,” the authors wrote. “To this end, using several in vitro and in vivo models, we explored the presence and functional contributions of IGFBP2 in senescence-mediated lung fibrosis.”
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The research team employed gene silencing and overexpression to explore the role of IGFBP2 proteins in human and mouse pulmonary fibrosis cells. Recombinant IGFBP2 delivered intranasally reduced fibrosis and proinflammatory mediators and inhibited senescence in a bleomycin-induced aged mouse model of IPF.
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Furthermore, the authors found reduced expression of IGFBP2 in AEC2 cells from human patients with IPF compared with that of AEC2 cells from patients with chronic obstructive pulmonary disease (COPD) or hypersensitivity pneumonitis (HP).
Given that peroxisome proliferator-activated receptor α (PPARα) is known to be a transcription factor for IGFBP2, the authors demonstrated decreased PPARα expression in AEC2 cells after bleomycin injury compared with that of cells treated with saline. In addition, PPARα expression levels were significantly lower in AEC2 cells from human patients with IPF than in those from patients with COPD or HP.
These results indicate that PPARα might have therapeutic potential in IPF.
The authors caution that patient samples were all from a single center and were only from individuals with end-stage IPF. However, they conclude that the loss of IGFBP2 in IPF appears to mediate senescence via PPARα expression to promote fibrosis, and, therefore, restoring IDGBP2 levels could be an effective therapeutic approach for these patients.
Reference
Chin C, Ravichandran R, Sanborn K, et al. Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis. Cell Rep Med. Published online February 13, 2023. doi:10.1016/j.xcrm.2023.100945
