Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
Department of Anesthesiology, Shanghai Children's Medical Center, Shanghai Jiao‑Tong University School of Medicine, Shanghai 200127, P.R. China.
Int J Mol Med. 2019 Mar;43(3):1217-1228. doi: 10.3892/ijmm.2019.4067. Epub 2019 Jan 17.
Mechanical ventilation may cause ventilator‑induced lung injury (VILI). Canonical Wnt signaling has been reported to serve an important role in the pathogenesis of VILI. Bioinformatics analysis revealed that canonical and non‑canonical Wnt signaling pathways were activated in VILI. However, the role of non‑canonical Wnt signaling in the pathogenesis of VILI remains unclear. The present study aimed to analyze the potential role of non‑canonical Wnt signaling in VILI pathogenesis. Lung injury was assessed via Evans blue albumin permeability and histological scoring, as well as by inflammatory cytokine expression and total protein concentration in bronchoalveolar lavage fluid. The relative protein expression of canonical and non‑canonical Wnt signaling pathway components were examined via western blotting and immunohistochemistry. The results demonstrated that 6 h of mechanical ventilation at low tidal volume (LTV; 6 ml/kg) or moderate tidal volume (MTV; 12 ml/kg) induced lung injury in sensitive A/J mice. Ventilation with MTV increased the protein levels of Wnt‑induced secreted protein 1 (WISP1), Rho‑associated protein kinase 1 (ROCK1), phosphorylated (p)‑Ras homolog gene family, member A and p‑C‑Jun N‑terminal kinase (JNK). Inhibition of ROCK1 by Y27632 and JNK by SP600125 attenuated MTV‑induced lung injury and decreased the expression of proteins involved in non‑canonical Wnt signaling, including WISP1. In conclusion, non‑canonical Wnt signaling participates in VILI by modulating WISP1 expression, which has been previously noted as critical for VILI development. Therefore, the non‑canonical Wnt signaling pathway may provide a preventive and therapeutic target in VILI.
机械通气可能导致呼吸机相关性肺损伤（VILI）。经典 Wnt 信号通路已被报道在 VILI 的发病机制中起重要作用。生物信息学分析显示，经典和非经典 Wnt 信号通路在 VILI 中被激活。然而，非经典 Wnt 信号在 VILI 发病机制中的作用尚不清楚。本研究旨在分析非经典 Wnt 信号在 VILI 发病机制中的潜在作用。通过 Evans 蓝白蛋白通透性和组织学评分以及支气管肺泡灌洗液中炎症细胞因子表达和总蛋白浓度评估肺损伤。通过 Western blot 和免疫组织化学检测经典和非经典 Wnt 信号通路成分的相对蛋白表达。结果表明，低潮气量（6ml/kg）或中潮气量（12ml/kg）机械通气 6h 可诱导敏感 A/J 小鼠肺损伤。与 MTV 通气相比，WISP1、Rho 相关蛋白激酶 1（ROCK1）、磷酸化（p）-Ras 同源基因家族成员 A 和 p-C-Jun N-末端激酶（JNK）的蛋白水平增加。用 Y27632 抑制 ROCK1 和用 SP600125 抑制 JNK 可减轻 MTV 诱导的肺损伤，并降低非经典 Wnt 信号通路相关蛋白（包括 WISP1）的表达。总之，非经典 Wnt 信号通过调节 WISP1 的表达参与 VILI，先前的研究表明 WISP1 对 VILI 的发展至关重要。因此，非经典 Wnt 信号通路可能为 VILI 提供预防和治疗靶点。
