Defensive Role Of Gab1Against Lung Fibrotic Injury Through Regulating Surfactant Homeostasis

1. Aims and SignificanceSurfactant proteins play defensive role in alveolar homeostasis in pathologic conditions as acute or chronic lung injuries, despite the physiologic functions of maintaining pulmonary compliance and ventilation. Type II epithelia (AT-II) cells are specifically responsible for surfactant protein production and thus play central role against lung injury. Disruption of lung injury-repair balance companied with abnormal signaling are considered initiation for irreversible chronic lung injury after acute injury stimulation. Gabl is a major member of the Dos/Gab subfamily scaffolding molecules and regulates proliferation, development, inflammation and angiogenesis in multiple organs. Gab1provides rich binding sites for SH2and SH3domains, and is believed to operate downstream of receptors for various growth factors and cytokines. Recent studies show that Gabl is a major susceptibility loci for pulmonary inflammatory disease. Herein we looked into the characteristics of Gabl in the whole process of lung inflammatory injury. 2MethodsIn this study, we firstly examined reduced surfactant levels by knocking down Gabl in mouse type II alveolar epithelia (AT-Ⅱ) cell line, and demonstrated inhibited survival signaling pathways which required for lung repair. To further investigate the role of Gab1in vivo, we generated Gab1conditional knockout in type II epithelia (Gab1△/△). Using bleomycin induced fibrosis model, we looked into the phenotypes that Gab1△/△revealed. Gabl mutant plasmids were constructed to investigate potential pathways that Gab1participates in regulating lung homeostasis.3. Results3.1Gab1△/△mice exhibited reduction of surfactant proteins, impaired pulmonary compliance and defected lamellar bodies observed in AT-IⅡs;3.2Gab1△/△mice revealed severer injury in BLM-induced chronic lung injury model;3.3Gab1deficien blocked signal transductions that required for lung repair;3.4Overexpressing Gab1mutants impaired surfactant synthesis.4. Conclusions:4.1Gab1deficiency blocks surfactant synthesis and impairs pulmonary compliance;4.2Gab1△/△is much more susceptible to BLM stimulation and revealed a severer fibrotic injury;4.3Gab1plays critical role in signal transductions which required for lung repair;4.4Gab1regulates surfactant synthesis and prevents from susceptibility mainly through SHP2or PI3K pathway.