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

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.

Characterization of the acute inflammatory profile and resolution of airway inflammation after Igf1r-gene targeting in a murine model of HDM-induced asthma

“…Additionally, decreased eosinophilopoiesis in bone marrow of Igf1r deficient mice can also substantially contribute to reduced eosinophil presence in the lung. The proposed mechanism illustrated in this figure is supported by results from the present study and additional reports [ 12 , 20 , 28 , 29 , 36 , 38 ].…”

“…Additional reports have shown that IL33 exacerbates murine allergic bronchoconstriction and that resolution of allergic airway inflammation and AHR is dependent upon disruption of IL33 signaling in mice [ 27 , 28 ]. Notably, lung epithelial-specific Igf1r deficiency in mice caused delayed differentiation of the airway epithelium, a major source of IL33 [ 29 , 30 ]. IGF1R - deficient lungs showed a reduced proportion of club cells in distal airways after chronic HDM exposure [ 12 ] and therefore this phenomenon could be manifested as a reduced IL33 release from the airway epithelium by HDM.…”

“…In accordance, blockade of FOXM1 activity in mice after HDM exposure led to reduced goblet cell hyperplasia and decreased number of eosinophils in BALF [ 39 , 40 ]. Furthermore, we recently demonstrated that lung epithelial-specific Igf1r deficiency in mice and chronically HDM-challenged IGF1R-depleted mice showed delayed club cell differentiation which could result in decreased goblet cell hyperplasia and mucus production [ 12 , 29 ].…”

Attenuated airway hyperresponsiveness and mucus secretion in HDM‐exposed Igf1r‐deficient mice

“…The upregulation of Igf1, Insr, Igfbp3, and Igfbp5 in PBS-exposed mice is possibly a compensatory effect in response to Igf1r deficiency, as we have previously reported in lungs from mice with compromised Igf1r signaling in the respiratory epithelium. 13 Accordingly, it has been previously reported that exogenous Igfbp3 and Igfbp5 administration blocks physiological consequences of asthma in OVA-challenged mice and enhances epithelial cell adhesion to maintain the epithelial-mesenchymal boundary. 8,9,16 Thus, Igfbp3 and Igfbp5 could mediate protective properties against HDM-mediated allergic inflammation.…”

“…The reduced proportion of club cells found in distal airways of CreERT2 mutant lungs is in accordance with recent data published by our group where a lung epithelial-specific Igf1r deficiency in mice caused delayed differentiation of club cells in terminal bronchioles. 13 In response to allergen stimulation, club cells differentiate into goblet cells through transcriptional activation of the master regulator Spdef.…”