Involvement of Igf1r in Bronchiolar Epithelial Regeneration: Role during Repair Kinetics after Selective Club Cell Ablation

• Published in: PloS one 2016-11, Vol.11 (11), p.e0166388-e0166388
• Main Authors: López, Icíar P, Piñeiro-Hermida, Sergio, Pais, Rosete S, Torrens, Raquel, Hoeflich, Andreas, Pichel, José G
• Format: Article
• Language: English
• Subjects: Ablation; Alveoli; Analysis; Animals; Asthma; Biology and Life Sciences; Biomarkers; Bronchioles - physiology; Cancer therapies; Cell cycle; Cell differentiation; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell growth; Cell injury; Cell Proliferation; Chronic obstructive pulmonary disease; Cytology; Differentiation; Epithelial cells; Epithelium; Fibrosis; Gene Expression; Gene Knockout Techniques; Growth factors; Homeostasis; Immunohistochemistry; Insulin; Insulin-like growth factor I; Insulin-like growth factor-binding protein 3; Insulin-like growth factors; Kinases; Kinetics; Ligands; Localization; Lung - metabolism; Lung cancer; Lung diseases; Lungs; Macrophages; Medicine and Health Sciences; Mice; Mice, Transgenic; Morphogenesis; Muscles; Mutants; Mutation; Naphthalene; Naphthalenes - pharmacology; Ontogeny; Organ Specificity - genetics; Physical Sciences; Proteins; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Regeneration; Repair; Research and Analysis Methods; Respiratory Mucosa - physiology; Respiratory tract; Restoration; Rodents; Senescence; Signal Transduction - drug effects; Signaling; Smooth muscle; Somatomedins - genetics; Somatomedins - metabolism; Wound Healing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0166388

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.