Abstract
Regeneration of lung epithelium is vital for maintaining airway function and integrity. An imbalance between epithelial damage and repair is at the basis of numerous chronic lung diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. IGF (Insulin-like Growth Factors) signaling has been associated with most of these respiratory pathologies, although their mechanisms of action in this tissue remain poorly understood. Expression profiles analyses of IGF system genes performed in mouse lung support their functional implication in pulmonary ontogeny. Immuno-localization revealed high expression levels of Igf1r (Insulin-like Growth Factor 1 Receptor) in lung epithelial cells, alveolar macrophages and smooth muscle. To further understand the role of Igf1r in pulmonary homeostasis, two distinct lung epithelial-specific Igf1r mutant mice were generated and studied. The lack of Igf1r disturbed airway epithelial differentiation in adult mice, and revealed enhanced proliferation and altered morphology in distal airway club cells. During recovery after naphthalene-induced club cell injury, the kinetics of terminal bronchiolar epithelium regeneration was hindered in Igf1r mutants, revealing increased proliferation and delayed differentiation of club and ciliated cells. Amid airway restoration, lungs of Igf1r deficient mice showed increased levels of Igf1, Insr, Igfbp3 and epithelial precursor markers, reduced amounts of Scgb1a1 protein, and alterations in IGF signaling mediators. These results support the role of Igf1r in controlling the kinetics of cell proliferation and differentiation during pulmonary airway epithelial regeneration after injury.
Highlights
Adult resident stem or progenitor cells are implicated in both homeostatic tissue maintenance and functional restoration after injury in many organs, including the lung
Whereas Igf1r showed a sustained constitutive expression, with a moderate peak at P1, Igf2r, Igf1, Igf2 and Insr expression levels were found to be high during embryonic development, decreasing after P1
We noticed a lack of Igf1r expression in the proximal airwayepithelial cells of these mutants, though they were found only in discrete areas and at a low frequency. These results indicate that Cre-mediated Igf1r deletion occurred in a mosaic pattern in airway epithelial cells, with the best efficiency found in terminal bronchioles, in areas close to bronchioalveolar duct junction (BADJ)
Summary
Adult resident stem or progenitor cells are implicated in both homeostatic tissue maintenance and functional restoration after injury in many organs, including the lung. The lung reaches a steady state in which epithelial turnover is low. Airway epithelial cells are constantly exposed to and damaged by potential toxic agents and pathogens in the environment, and their subsequent regeneration is a vital process in helping maintain.
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