1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
2 Department of Anesthesia and Critical Care, University of Turin, AOU Città della Salute e della Scienza di Torino-Ospedale Molinette, Turin, Italy.
Am J Respir Crit Care Med. 2015 Aug 1;192(3):315-23. doi: 10.1164/rccm.201412-2326OC.
Lung-protective ventilatory strategies have been widely used in patients with acute respiratory distress syndrome (ARDS), but the ARDS mortality rate remains unacceptably high and there is no proven pharmacologic therapy.
Mechanical ventilation can induce oxidative stress and lung fibrosis, which may contribute to high dependency on ventilator support and increased ARDS mortality. We hypothesized that the novel cytokine, midkine (MK), which can be up-regulated in oxidative stress, plays a key role in the pathogenesis of ARDS-associated lung fibrosis.
Blood samples were collected from 17 patients with ARDS and 10 healthy donors. Human lung epithelial cells were challenged with hydrogen chloride followed by mechanical stretch for 72 hours. Wild-type and MK gene-deficient (MK(-/-)) mice received two-hit injury of acid aspiration and mechanical ventilation, and were monitored for 14 days.
Plasma concentrations of MK were higher in patients with ARDS than in healthy volunteers. Exposure to mechanical stretch of lung epithelial cells led to an epithelial-mesenchymal transition profile associated with increased expression of angiotensin-converting enzyme, which was attenuated by silencing MK, its receptor Notch2, or NADP reduced oxidase 1. An increase in collagen deposition and hydroxyproline level and a decrease in lung tissue compliance seen in wild-type mice were largely attenuated in MK(-/-) mice.
Mechanical stretch can induce an epithelial-mesenchymal transition phenotype mediated by the MK-Notch2-angiotensin-converting enzyme signaling pathway, contributing to lung remodeling. The MK pathway is a potential therapeutic target in the context of ARDS-associated lung fibrosis.
保护性通气策略已广泛应用于急性呼吸窘迫综合征（ARDS）患者，但 ARDS 的死亡率仍然高得令人无法接受，并且没有经过验证的药物治疗方法。
机械通气可引起氧化应激和肺纤维化，这可能导致对呼吸机支持的高度依赖和 ARDS 死亡率增加。我们假设新型细胞因子 midkine（MK）可在氧化应激中上调，在 ARDS 相关肺纤维化发病机制中起关键作用。
采集了 17 例 ARDS 患者和 10 例健康供者的血液样本。用氯化氢处理人肺上皮细胞，然后机械拉伸 72 小时。野生型和 MK 基因敲除（MK(-/-)）小鼠接受酸吸入和机械通气的双重打击，并监测 14 天。
ARDS 患者的血浆 MK 浓度高于健康志愿者。肺上皮细胞的机械拉伸导致与血管紧张素转换酶表达增加相关的上皮-间充质转化表型，该表型可通过沉默 MK、其受体 Notch2 或 NADP 还原氧化酶 1 得到减弱。在野生型小鼠中观察到胶原沉积和羟脯氨酸水平增加以及肺组织顺应性降低，而在 MK(-/-)小鼠中则得到了很大的缓解。
机械拉伸可诱导由 MK-Notch2-血管紧张素转换酶信号通路介导的上皮-间充质转化表型，导致肺重塑。MK 途径是 ARDS 相关肺纤维化治疗的潜在靶点。
