Igf1r deficiency attenuates acute inflammatory response and oxidative stress following bleomycin-induced lung injury. Mus musculus

IGF1R (Insulin-like Growth Factor 1 Receptor) is a ubiquitously expressed transmembrane tyrosine kinase receptor with multiple functions including inflammation. IGF activity maintains human lung homeostasis, being involved in relevant pulmonary diseases with an inflammatory component, such as lung cancer, COPD, asthma and pulmonary fibrosis. Here we examined the role of IGF1R in lung inflammation using mice with a postnatal deficiency of Igf1r and a model of bleomycin(BLM)-induced lung injury. Lung transcriptome analysis of Igf1r-deficient mice showed a general inhibition of transcription of genes related to epigenetics, inflammation/immune response and oxidative stress activity with potential pulmonary protective roles. Early upon intratracheal BLM treatment, mutant mice showed improved survival and milder pulmonary injury and inflammation. Their lungs presented down-regulation of macrophage (Marco/Adgre1), neutrophil-related (Cxcl1/Ly6g), pro-inflammatory (Tnf/Il1b/Il6), endothelial adhesion (Icam1/Pecam1) and alveolar damage (Aqp5/Sftpc) markers and up-regulation of resolution phase markers (Csf1/Il13/Cd209a). Changes in mRNA of IGF system genes were also found, in parallel to a hindered response to hypoxia (Hif1a) and increased expression of the anti-oxidative stress marker Gpx8. These findings identify Igf1r as an important player in oxidative stress and inflammation and suggest that targeting Igf1r may block the inflammatory response in lung diseases with this component. Overall design: Lung mRNA profiles of 2 months-old Igf1rfl/fl normal/control transgenic mice and UBC-CreERT2; Igf1rfl/fl Igf1r-deficient mice were generated by deep sequencing using Illumina GAIIx.

胰岛素样生长因子1受体（Insulin-like Growth Factor 1 Receptor，IGF1R）是一种广泛表达的跨膜酪氨酸激酶受体，具备包括炎症调控在内的多种功能。胰岛素样生长因子（IGF）信号可维持人类肺脏内稳态，并参与多种伴有炎症组分的肺部疾病，例如肺癌、慢性阻塞性肺疾病（Chronic Obstructive Pulmonary Disease，COPD）、哮喘以及肺纤维化。
本研究通过构建出生后敲除Igf1r的小鼠模型以及博来霉素（bleomycin, BLM）诱导的肺损伤模型，探究了IGF1R在肺部炎症中的作用。
对Igf1r敲除小鼠的肺组织转录组分析显示，与表观遗传调控、炎症/免疫应答及氧化应激相关的基因转录普遍受到抑制，而这类基因可能发挥肺部保护作用。
在气管内给予博来霉素早期，基因敲除小鼠展现出更高的生存率，且肺部损伤与炎症反应更轻微。其肺组织中巨噬细胞相关标志物（Marco/Adgre1）、中性粒细胞相关标志物（Cxcl1/Ly6g）、促炎因子（Tnf/Il1b/Il6）、内皮黏附分子（Icam1/Pecam1）及肺泡损伤标志物（Aqp5/Sftpc）的表达均出现下调，而炎症消退阶段标志物（Csf1/Il13/Cd209a）的表达则上调。
研究同时发现胰岛素样生长因子系统相关基因的mRNA表达发生改变，小鼠对缺氧的应答受到抑制（Hif1a），且抗氧化应激标志物Gpx8的表达升高。
上述研究结果证实，Igf1r是氧化应激与炎症反应中的关键调控因子，提示靶向Igf1r或许可以阻断伴有炎症组分的肺部疾病的炎症应答。
实验整体设计：本研究通过Illumina GAIIx平台进行深度测序，获取了2月龄的Igf1rfl/fl正常/对照转基因小鼠与UBC-CreERT2; Igf1rfl/fl Igf1r敲除小鼠的肺组织mRNA表达谱。