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Deficiency Tsc1 in Alveolar Epithelial Cell Aggravates Bleomycin-Induced Pulmonary Inflammation in Mice

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A7739 - Deficiency Tsc1 in Alveolar Epithelial Cell Aggravates Bleomycin-Induced Pulmonary Inflammation in Mice
Author Block: A. Ma1, J. Li1, Q. Liu1, Y. Jiang2, K. Xu3; 1The first affiliated hospital of Xiamen University, Xiamen, China, 2Department of Respiratory Medicine, Haicang Hospital, Xiamen, China, 3Peking Union Medical College Hospital, Beijing, China.
Rationale: Injury and repair of alveolar epithelial cells (AECs) are involved in the pathogenesis of acute lung inflammation and pulmonary fibrosis. mTOR signaling pathway plays an important role in cell differentiation and proliferation. The aberrant activity of mechanistic target of rapamycin (mTOR) pathway is observed in alveolar epithelium of idiopathic pulmonary fibrosis (IPF) and acute lung injury (ARDS) patients. However, the role of mTOR in the pathogenesis of pulmonary injury remains unresolved. Methods: A SPC-Cre expression construct was established in order to generate the SPC-Cre transgene mice. Using the Cre/Loxp transgenic gene system to generate SPC-Cre/Tsc1-/- mice which deficiency of Tsc1 activated mTOR signaling pathway in AECs. X-gal staining was performed and pulmonary fibrosis was induced by single intra-trachea instillation of bleomycin. Also, survival curve was record and bronchoalveolar lavage fluid (BALF) was collected in mice. Total cell counts, cellular differentials were determined using a hemocytometer and stained with Diff-Quik for cellular differentials. mTOR pathway activity in lung was assessed by western blot analysis and qRT-PCR was used to examine mRNA levels of cytokines in lung tissue. Results: We generated SPC-Cre/Tsc1-/- transgenic mouse line, in which mTOR was upregulated in alveolar epitheliums. We found that alveolar space was significantly larger in SPC-Cre/Tsc1-/- mice measured with mean linear intercept (MLI). Although deficiency of Tsc1 in alveolar epithelium disrupted the alveolarization, the mouse line of SPC-Cre/Tsc1-/- appeared normal and was fertile after birth. After bleomycin administration, the numbers of inflammation cells in bronchoalveolar lavage fluid (BALF) was markedly increased. However, no significant difference was observed in mortality and Ashcroft score of pulmonary fibrosis between SPC-Cre/Tsc1-/- mice and controls. Also, there were no differences in the content of hydroxyproline and the levels of profibrotic cytokines compared with controls. Pretreatment of rapamycin ameliorated bleomycin-induced pulmonary inflammation, failed to fibrosis in SPC-Cre/Tsc1-/- mice. Conclusions: We conclude that mTOR is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for alveolarization and bleomycin-induced lung inflammation in mice.
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