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

描述（由申请人提供）：急性肺损伤（ALI）是一种毁灭性疾病，发病率和死亡率非常高，治疗选择有限。对机械通气（MV）（ALI的主要支持治疗）有害作用的认识，导致对呼吸机相关肺损伤（VALI）中观察到的肺血管通透性相关通路的兴趣日益增加。低潮气量肺策略仍然是ALI/VALI的唯一支持性治疗，已证实有效。因此，需要特异性靶向阿利亚/ALI中屏障破坏机制的新疗法。内皮细胞凋亡最近被认为是VALI早期发病机制中的一个必要事件。此外，p38丝裂原活化蛋白（MAP）激酶，一种已知的内皮细胞凋亡介导因子，在MV的损伤模式下被激活。然而，p38 MAP激酶的下游效应参与介导VALI的发展和严重程度仍然未知。p38 MAP激酶及其下游效应物MAPK活化蛋白激酶MK2（MK2）的活化导致小热休克蛋白27（HSP 27）的磷酸化，HSP 27是已知的凋亡调节剂。此外，HSP 25（HSP 27的鼠同源物）的磷酸化与HVT MV介导的细胞凋亡和肺水肿相关。然而，MK2或HSP 25促进VALI发展的具体机制尚不清楚。该提议将使用体外机械应力模型和野生型和MK 2-/-小鼠中建立的VALI鼠模型来检验以下假设：MK 2介导的HSP 27磷酸化对于促进HVT MV介导的细胞凋亡和由此产生的肺水肿至关重要。本申请的具体目的是：1）确定MK 2在体外促进机械应力诱导的细胞凋亡中的作用; 2）确定HSP 25/27磷酸化在体外机械应力诱导的细胞凋亡中的作用;和3）确定HSP 25/27磷酸化在体内HVT MV介导的细胞凋亡和所得肺血管通透性中的作用。相关性（参见说明）：尽管机械通气是许多疾病治疗的基石，但它有可能加重并导致新发肺损伤。我们已经确定了一个途径和一个潜在的机制，是相关的介导损伤，由于机械通气。我们希望进一步的了解将有助于确定新的治疗靶点。 (End摘要）

DESCRIPTION (provided by applicant): 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. (End of Abstract)