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The Role of Gab1for Pulmonary Alveolar Surfactant Homeostasis in the Prevention of Acute Luns Injury

Author: ZuoLi
Tutor: KeYueHai
School: Zhejiang University
Course: Pathology and Pathophysiology
Keywords: acute lung injury lipopolysaccharide Gab1 pulmonary surfactant protein
CLC: R563.8
Type: Master's thesis
Year: 2012
Downloads: 38
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Abstract


Background:Acute lung injury, a pulmonary complication induced by infection, shock and wound, may develop to the acute respiration distress syndrome (ARDS). ALI was clinically featured as serious hypoxemia, diffuse pulmonary soakage and the descent of pulmonary compliance. Despite numerous studies on ALI over decades, few therapeutic strategies have emerged, and the current efficienttreatment options remain limited. Grb2-ssociated binding protein1(Gabl),as a docking protein, associated with several receptor tyrosine kinases, has been previously demonstrated to be an important signal regulator trasnduingmultiple molecular events. Numerous genes that cause injury/apoptosis of type II alveolar epithelial cells have been identified in ALI. It’s much unclear about physiological functionof Gab1in the alveoli, in particular type II cells in pulmonary homeostasis.Objective:The present study aims to establish alveolar type II cells (AT-II) specific Gab1knockout miceusing Cre/LoxP system and to analyze phenotype, by which this study has been focused on exploringin vivo role of Gab1in maintaining pulmonary alveolar surfactant homeostasis in the prevention of ALI. Method:Transgenic mice specifically carrying SPCrtTA in alveolar epithelial type II cell were intercrossed with tetO/cre mice to obtain SPCrtta-Teto ere. Then the SPCrtta-Teto ere mice was mated with a mouse strain that carries Gab1conditional alleles(Ga6lflox/flox) to obtain the alveolar epithelial type II cell specific Gab1knockout mice (SPCrtTA-TetoCre; Gablflox/flox). the triple transgenic mice were generated for the inducible disruption of Gabl in the alveolar epithelium to explore the physiological roles of Gabl. Dox was administered to these animals to specifically target the type II epithelium for disrupting the expression of Gabl. The deletion of Gab1in alveolar epithelial type II cell appears normal, however the mice received LPS administration exhited severe pathological alterations on pulmonary alveoli. The loss of Gab1in lung epithelia was assessed by assaying mRNA and protein levels and comparing those levels to the control, the extent of ALI was assessed by histology and ELISA measurement.Measurements:(1) Mice airways responsiveness was measured in vivo after Dox treatment on day7,the last aerosol exposure by means of Plethysmography.(2) The lung was lavaged with saline, and the total number of leukocyte in BALF was counted.(3) Pathological section were of trachea, bronchia and lung, which fixed by10%formalin. The change of inflammation in airway tissue was investigated after being stained with HE. (4) Immunohistochemistry dye was made with the Envision two-step method.(5) SPs in mouse’s lung tissue was extracted and measured with Western blot and Realtime-PCR analysis.(6) Measurement data was express as mean±SD and analysis with t-test.Result:In ALI after lung tissue slice, the result of HE staining show the lung tissue morphology fundamental normal in Gabl knockout mice, and model group consistent with the change of ALI. Gab1knockout mice exhibit impaired alveolar function and decrease of pulmonary surfactant proteins, and the mice are sensitive to LPS-induced inflammation.Conclusion:(1) We generated the inducible lung alveolus-specific Gabl knockout in which Gabl gene was selectively disrupted in AT-II.(2) Mice lacking Gabl exhibit impaired alveolar function and decreased expression of pulmonary surfactant proteins.(3) In LPS induced ALI mouse model, Gabl knockout mice are more sensitive to inflammation response.

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CLC: > Medicine, health > Internal Medicine > Respiratory system and chest diseases > Pulmonary disease > Respiratory failure
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