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

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 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. Lung mRNA profiles of 3 months-old Igf1rfl/fl normal/control transgenic mice were generated by deep sequencing using Illumina GAIIx. ------------------------------------------- Submitter states "we use data on the absolute transcription levels (FPKM) of same IGF system genes on the adult "normal" mouse lung to compare them with those reported in the human adult lung (expressed in both as FPKM) (http://www.proteinatlas.org/)".肺上皮细胞再生对于维持气道功能与结构完整性至关重要。上皮损伤与修复之间的失衡，是诸多慢性肺部疾病（如哮喘、慢性阻塞性肺疾病（Chronic Obstructive Pulmonary Disease, COPD）、肺纤维化及肺癌）的发病基础。胰岛素样生长因子（Insulin-like Growth Factors, IGF）信号通路已与多数这类呼吸道病理过程相关联，尽管其在该组织中的作用机制仍有待阐明。 针对小鼠肺部IGF系统基因的表达谱分析，证实了其在肺脏发生过程中的功能意义。免疫定位实验显示，胰岛素样生长因子1受体（Insulin-like Growth Factor 1 Receptor, Igf1r）在肺上皮细胞、肺泡巨噬细胞和平滑肌中呈高表达水平。 为进一步阐明Igf1r在肺部稳态维持中的作用，研究人员构建并研究了两种肺上皮细胞特异性敲除Igf1r的突变小鼠模型。研究发现，Igf1r缺失会干扰成年小鼠的气道上皮分化，表现为远端气道克拉拉细胞增殖增强且形态异常。 在萘（naphthalene）诱导的克拉拉细胞损伤后的修复过程中，Igf1r突变小鼠的终末细支气管上皮再生动力学受到阻滞，表现为克拉拉细胞和纤毛细胞的增殖水平升高、分化延迟。 在气道修复期间，Igf1r缺陷小鼠的肺部可见Igf1（Insulin-like Growth Factor 1, Igf1）、胰岛素受体（Insulin receptor, Insr）、胰岛素样生长因子结合蛋白3（Insulin-like Growth Factor Binding Protein 3, Igfbp3）及上皮前体细胞标志物的表达水平上调，克拉拉细胞分泌蛋白1A1（Scgb1a1）的含量降低，同时IGF信号通路介导因子也出现异常。 上述结果证实，Igf1r在损伤后肺部气道上皮再生过程中，对细胞增殖与分化的动力学调控发挥着关键作用。研究采用Illumina GAIIx测序平台通过深度测序，获取了3月龄Igf1rfl/fl正常/对照转基因小鼠的肺部mRNA表达谱。 ------------------------------------------- 提交者注明：“我们使用成年"normal"小鼠肺部同一IGF系统基因的绝对转录水平（FPKM），与人类成人肺部的相关数据（二者均以FPKM表示，来源：http://www.proteinatlas.org/）进行对比分析。”