Mei Shuya, Tang Ri, Hu Yue, Feng Jinhua, Xu Qiaoyi, Zhou Yang, Zhong Han, Gao Yuan, He Zhengyu, Xing Shunpeng
Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Lab Invest. 2023 Jan;103(1):100021. doi: 10.1016/j.labinv.2022.100021.
Mechanical ventilation (MV) has become a clinical first-line treatment option for patients with respiratory failure. However, it was unclear whether MV further aggravates the process of sepsis-associated pulmonary fibrosis and eventually leads to sepsis and mechanical ventilation-associated pulmonary fibrosis (S-MVPF). This study aimed to explore the mechanism of S-MVPF concerning integrin β3 activation in glycometabolic reprogramming of lung fibroblasts. We found that MV exacerbated sepsis-associated pulmonary fibrosis induced by lipopolysaccharide, which was accompanied by proliferation of lung fibroblasts, increased deposition of collagen in lung tissue, and increased procollagen type I carboxy-terminal propeptide in the bronchoalveolar lavage fluid. A large number of integrin β3- and pyruvate kinase M2-positive fibroblasts were detected in lung tissue after stimulation with lipopolysaccharide and MV, with an increase in lactate dehydrogenase A expression and lactate levels. S-MVPF was primarily attenuated in integrin β3-knockout mice, which also resulted in a decrease in the levels of pyruvate kinase M2, lactate dehydrogenase A, and lactate. In conclusion, MV aggravated sepsis-associated pulmonary fibrosis, with glycometabolic reprogramming mediated by integrin β3 activation. Thus, integrin β3-mediated glycometabolic reprogramming might be a potential therapeutic target for S-MVPF.
机械通气（MV）已成为呼吸衰竭患者的临床一线治疗选择。然而，MV是否会进一步加重脓毒症相关的肺纤维化并最终导致脓毒症和机械通气相关的肺纤维化（S-MVPF）尚不清楚。本研究旨在探讨S-MVPF在肺成纤维细胞糖代谢重编程中与整合素β3激活相关的机制。我们发现，MV加剧了脂多糖诱导的脓毒症相关肺纤维化，这伴随着肺成纤维细胞的增殖、肺组织中胶原蛋白沉积的增加以及支气管肺泡灌洗液中I型前胶原羧基末端前肽的增加。在用脂多糖和MV刺激后，在肺组织中检测到大量整合素β3和丙酮酸激酶M2阳性的成纤维细胞，乳酸脱氢酶A表达和乳酸水平增加。S-MVPF在整合素β3基因敲除小鼠中主要减轻，这也导致丙酮酸激酶M2、乳酸脱氢酶A和乳酸水平降低。总之，MV加重了脓毒症相关的肺纤维化，其通过整合素β3激活介导糖代谢重编程。因此，整合素β3介导的糖代谢重编程可能是S-MVPF的一个潜在治疗靶点。
