Integrated Stress Response Mediates Epithelial Injury in Mechanical Ventilation
Integrated Stress Response Mediates Epithelial Injury in Mechanical Ventilation
复制标题
整合应激反应介导机械通气中的上皮损伤
DOI：
10.1165/rcmb.2016-0404oc
复制
发表时间：
2017-08-01
影响因子：
6.4
通讯作者：
Margulies, Susan S.
中科院分区：
文献类型：
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作者：
Dolinay, Tamas;Himes, Blanca E.;Margulies, Susan S.
呼吸机诱导的肺损伤（VILI）是机械通气的严重并发症，可导致急性呼吸窘迫综合征。VILI的特征是上皮屏障受损，随后发生肺水肿和严重缺氧。现有的肺保护性呼吸机策略在预防VILI方面仅提供适度的益处，因为它们不能阻止肺泡过度扩张和伴随的炎症肺区域的上皮屏障功能障碍。目前没有有效的生化疗法来减轻肺泡上皮的损伤。我们假设肺泡牵张激活了综合应激反应（ISR）通路，并且该通路的化学抑制减轻了牵张和机械通气期间肺泡屏障的破坏。使用我们建立的大鼠原代I型样肺泡上皮细胞单层拉伸模型和模拟急性呼吸窘迫综合征中肺泡过度扩张的体内大鼠机械通气，我们研究了上皮细胞对机械应力的反应。我们的研究表明，ISR信号通路是上皮通透性的关键调节因子。我们发现，长时间的上皮拉伸和有害的机械通气激活ISR，导致肺泡通透性增加，细胞死亡和促炎信号。化学抑制蛋白激酶RNA样内质网激酶，一个上游调节的途径，导致减少损伤信号和改善屏障功能后，长时间的周期性拉伸和损伤性机械通气。我们的研究结果提供了新的证据，即靶向治疗ISR可以减轻VILI。
Ventilator-induced lung injury (VILI) is a severe complication of mechanical ventilation that can lead to acute respiratory distress syndrome. VILI is characterized by damage to the epithelial barrier with subsequent pulmonary edema and profound hypoxia. Available lung-protective ventilator strategies offer only a modest benefit in preventing VILI because they cannot impede alveolar overdistension and concomitant epithelial barrier dysfunction in the inflamed lung regions. There are currently no effective biochemical therapies to mitigate injury to the alveolar epithelium. We hypothesize that alveolar stretch activates the integrated stress response (ISR) pathway and that the chemical inhibition of this pathway mitigates alveolar barrier disruption during stretch and mechanical ventilation. Using our established rat primary type I-like alveolar epithelial cell monolayer stretch model and in vivo rat mechanical ventilation that mimics the alveolar overdistension seen in acute respiratory distress syndrome, we studied epithelial responses to mechanical stress. Our studies revealed that the ISR signaling pathway is a key modulator of epithelial permeability. We show that prolonged epithelial stretch and injurious mechanical ventilation activate the ISR, leading to increased alveolar permeability, cell death, and proinflammatory signaling. Chemical inhibition of protein kinase RNA-like endoplasmic reticulum kinase, an upstream regulator of the pathway, resulted in decreased injury signaling and improved barrier function after prolonged cyclic stretch and injurious mechanical ventilation. Our results provide new evidence that therapeutic targeting of the ISR can mitigate VILI.