肺组织代谢重编程致乳酸清除障碍是致纤维化微环境形成、肺泡上皮细胞EMT启动和脓毒症相关性肺纤维化发生的关键环节，但机制不明。乳酸受体GPR81介导PGC-1α活化可上调MCT1并促进线粒体生物发生，通过“乳酸穿梭”过程加速肺泡上皮细胞清除乳酸。申请者发现LPS能抑制肺泡上皮细胞GPR81-PGC-1α通路活化和MCT1表达，由此推测LPS通过上述机制抑制肺泡上皮细胞线粒体生物发生并抑制细胞对乳酸的转运清除，促进致纤维化微环境形成，启动EMT和肺纤维化进程。本课题利用肺泡上皮细胞EMT和脓毒症相关性肺纤维化小鼠模型，研究LPS抑制肺泡上皮细胞清除乳酸，促进致纤维化微环境形成并启动EMT的机制，重点明确GPR81-PGC-1α通路、MCT1以及线粒体生物发生在以上过程中的作用，旨在从LPS抑制细胞间代谢交互作用促进致纤维化微环境形成的角度完善脓毒症相关性肺纤维化的机制，为该病早期防治奠定基础。

Metabolic reprogramming-induced lactate clearance disorder in lung tissue is crucial to the formation of fibrotic microenvironment, the initiation of alveolar epithelial cell(AEC) epithelial-mesenchymal transformation (EMT) and the progress of septic pulmonary fibrosis, however the underlying mechanism remains unknown. Activation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) mediated by GPR81, the lactate receptor, could upregulate MCT1 and induce mitochondrial biogenesis through “lactate shuttle” process to promote the clearance of lactate by AEC. Our previous studies revealed that LPS could inhibit activation of GPR81-PGC-1α pathway and expression of MCT1in AEC. Therefore, we speculate that LPS can inhibit AEC mitochondrial biogenesis as well as the transportation and clearance of lactate through the above mechanism and induce the formation of fibrotic microenvironment, the initiation of EMT and the progress of pulmonary fibrosis. In this study, based on the cellular model of LPS-induced AEC-EMT and the mice model of LPS-induced septic pulmonary fibrosis, we aim to explore the mechanism of LPS inhibiting the lactate clearance by AEC and promoting the formation of fibrotic microenvironment and the initiation of AEC-EMT. We especially focus on the role of GPR81-PGC-1α pathway, MCT1 upregulation and mitochondrial biogenesis play in the above process. Our research aims to explore the mechanism of septic pulmonary fibrosis from the perspective of LPS inhibiting the intercellular metabolic interaction and facilitating fibrotic microenvironment formation and lay foundation for the treatment of septic pulmonary fibrosis.