Integrin β3-PKM2 pathway-mediated aerobic glycolysis contributes to mechanical ventilation-induced pulmonary fibrosis.
Integrin β3-PKM2 pathway-mediated aerobic glycolysis contributes to mechanical ventilation-induced pulmonary fibrosis.
复制标题
整合素β3-PKM2 通路介导的有氧糖酵解有助于机械通气诱导的肺纤维化
作者：
Mei S;Xu Q;Hu Y;Tang R;Feng J;Zhou Y;Xing S;Gao Y;He Z
背景：机械通气（MV）可诱发肺纤维化。本研究旨在探讨 MV 诱导的肺纤维化是否与有氧糖酵解相关，并试图揭示整合素 β3-丙酮酸激酶 M2 (PKM2) 通路介导的潜在机制。方法：PKM2 敲低或抑制、整合素 β3 敲除或抑制以及野生型小鼠暴露于 MV (20 mL/kg) 2 h。结果：暴露于 MV 的小鼠肺组织中胶原蛋白沉积表达增加，α-平滑肌肌动蛋白和 I 型胶原蛋白上调。单细胞分析表明，MV 诱导的肺纤维化与肺成纤维细胞中整合素和糖酵解基因表达的增加以及代谢组学检测的糖酵解产物的上调有关。同时，通过蛋白质印迹和免疫组织化学证实整合素β3和PKM2的蛋白水平增加。双重免疫荧光染色和流式细胞分析显示肺组织中纤连蛋白+/整合素β3+和纤连蛋白+/PKM2+成纤维细胞数量增加。此外，用 PKM2 敲低 AAV 和抑制治疗后，或在整合素 β3 敲除和抑制小鼠中，MV 诱导的有氧糖酵解和肺纤维化得到改善。结论：整合素 β3-PKM2 通路介导的有氧糖酵解有助于 MV 诱导的肺纤维化。针对整合素 β3-PKM2 途径的有氧糖酵解的抑制可能是 MV 诱导的肺纤维化的有希望的治疗方法。
Background: Mechanical ventilation (MV) can induce pulmonary fibrosis. This study aims to investigate whether MV-induced pulmonary fibrosis is associated with aerobic glycolysis and seeks to uncover the underlying mechanisms mediated by integrin β3-pyruvate kinase M2 (PKM2) pathway. Methods: PKM2 knockdown or inhibition, integrin β3 knockout or inhibition and wild-type mice were exposed to MV (20 mL/kg) for 2 h. Results: Mice exposed to MV exhibited increased expression of collagen deposition, and upregulation of α-smooth muscle actin and collagen I in lung tissues. Single cells analysis showed that MV-induced pulmonary fibrosis was associated with increased gene expression of integrin and glycolysis in pulmonary fibroblasts, as well as upregulation of glycolytic products tested by metabolomics. Meanwhile, increased protein level of integrin β3 and PKM2 was confirmed by western blot and immunohistochemistry. Double immunofluorescence staining and flow cytometric analysis showed increased number of fibronectin+/integrin β3+ and fibronectin+/PKM2+ fibroblasts in lung tissues. Furthermore, MV-induced aerobic glycolysis and pulmonary fibrosis were ameliorated after treatment with PKM2 knockdown-AAV and inhibition, or in integrin β3 knockout and inhibition mice. Conclusions: Integrin β3-PKM2 pathway-mediated aerobic glycolysis contributes to MV-induced pulmonary fibrosis. The inhibition of aerobic glycolysis targeting integrin β3-PKM2 pathway may be a promising treatment for MV-induced pulmonary fibrosis.
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DOI：
10.1183/09031936.00196412
发表时间：
2014-01
期刊：
The European respiratory journal
影响因子：
--
作者：
Burnham EL;Janssen WJ;Riches DW;Moss M;Downey GP
通讯作者：
Downey GP
影响因子：
9.6
作者：
Li, Li-Fu;Chu, Pao-Hsien;Yang, Cheng-Ta
通讯作者：
Yang, Cheng-Ta
影响因子：
81.5
作者：
Matthay, Michael A.;Zemans, Rachel L.;Calfee, Carolyn S.
通讯作者：
Calfee, Carolyn S.
影响因子：
8.8
作者：
Cabrera-Benitez, Nuria E.;Parotto, Matteo;Slutsky, Arthur S.
通讯作者：
Slutsky, Arthur S.
影响因子：
5.2
作者：
Che P;Yu L;Friedman GK;Wang M;Ke X;Wang H;Zhang W;Nabors B;Ding Q;Han X
通讯作者：
Han X