MAP Kinase Signaling in Apoptosis-Induced Ventilator-Associated Lung Injury

急性肺损伤(ALI)是一种发病率和死亡率都很高、治疗效果有限的毁灭性疾病。 选择。对机械通气(MV)危害的认识--支持的支柱 ALI的治疗引起了人们对参与肺血管通透性的通路越来越感兴趣 观察呼吸机相关性肺损伤(VALI)。低潮气量肺策略仍然是唯一 ALI/VALI的支持性治疗已证实有效。因此，新的疗法将专门针对 Alia/ALI中涉及屏障破坏的机制是必要的。血管内皮细胞的凋亡 最近被认为是VALI早期发病机制中的一个必要事件。此外，p38有丝分裂原 激活的蛋白(MAP)激酶是一种已知的内皮细胞凋亡的媒介，它被激活以响应 MV的损伤模式。然而，p38 MAP激酶的下游效应器参与了介导 VALI的发展和严重程度尚不清楚。P38蛋白激酶及其下游的激活 效应分子MAPK激活的蛋白激酶MK2导致小分子热休克蛋白的磷酸化 27(HSP27)，已知的细胞凋亡调节因子。此外，热休克蛋白25(HSP27‘)的磷酸化对S小鼠的影响 同系物)与HVT MV介导的细胞凋亡和肺水肿相关。然而，具体的 MK2和HSP25在VALI发病中的作用机制(S)尚不清楚。这项建议 将检验MK2介导的HSP27的磷酸化对促进HVT MV至关重要的假设 使用体外机械应激模型和AN介导的细胞凋亡和由此导致的肺水肿 建立野生型和MK2-/-小鼠VALI模型。本申请的具体目标是： 1)明确MK2在体外促进机械应激诱导的细胞凋亡中的作用；2)确定MK2在促进机械应激诱导的细胞凋亡中的作用 HSP25/27在体外机械应激诱导的细胞凋亡中的磷酸化；以及3)确定HSP25/27的作用 HSP25/27磷酸化在HVT MV介导的大鼠肺血管通透性和细胞凋亡中的作用 活着。 相关性(请参阅说明)： 机械通风，虽然是治疗许多疾病的基石，但有可能 加重并引起新生的肺损伤。我们已经确定了一条途径和一种潜在的机制 与机械通风引起的损伤的调解有关。我们希望进一步的洞察将有助于识别小说 治疗靶点。

Acute lung injury (ALI) is a devastating illness with very high morbidity and mortality and limited therapeutic options. The recognition of the deleterious effects of mechanical ventilation (MV), the mainstay supportive therapy for ALI, has led to increasing interest in the pathways involved in pulmonary vascular permeability observed in ventilator-associated lung injury (VALI). Low tidal volume lung strategies remain the only supportive treatment of ALI/VALI with proven efficacy. Therefore, novel therapies that will specifically target mechanisms involved in barrier disruption in ALIA/ALI are needed. Endothelial cell apoptosis has been recently implicated as a necessary event in the early pathogenesis of VALI. Additionally, the p38 mitogen activated protein (MAP) kinase, a known mediator of endothelial cell apoptosis is activated in response to injurious modes of MV. However, the downstream effectors of p38 MAP kinase involved in mediating the development and severity of VALI remain unknown. Activation of p38 MAP kinase and its downstream effector MAPK-activated protein kinase MK2 (MK2) leads to phosphorylation of the small heat shock protein 27 (HSP27), a known regulator of apoptosis. In addition, phosphorylation of HSP25 (HSP27's murine homologue) correlates with HVT MV mediated apoptosis and pulmonary edema. However, the specific mechanism(s) by which MK2 or HSP25 contribute to the development of VALI are unknown. This proposal will test the hypothesis that MK2-mediated phosphorylation of HSP27 is critical for promoting HVT MV mediated apoptosis and resultant pulmonary edema using an in vitro mechanical stress model and an established murine model of VALI in wild type and MK2-/- mice. The specific aims of this application are to: 1) Define the role of MK2 in promoting mechanical stress-induced apoptosis in vitro; 2) Define the role of HSP25/27 phosphorylation in mechanical stress-induced apoptosis in vitro; and 3) Determine the role for HSP25/27 phosphorylation in HVT MV mediated apoptosis and resultant pulmonary vascular permeability in vivo. RELEVANCE (See instructions): Mechanical ventilation, although the cornerstone of treatment for many disorders, has the potential to exacerbate and cause de novo lung injury. We have identified a pathway and a potential mechanism that is relevant in mediating injury due to mechanical ventilation. We hope that further insight will help identify novel therapeutic targets.