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

描述（由申请人提供）：急性肺损伤（ALI）是一种具有很高发病率和死亡率的毁灭性疾病，治疗选择有限。机械通气（MV）是ALI的主要支持疗法，由于认识到其有害作用，人们对呼吸机相关肺损伤（VALI）中观察到的肺血管通透性通路的兴趣日益增加。低潮气量肺策略仍然是ALI/VALI唯一被证实有效的支持性治疗。因此，需要专门针对ALIA/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早期发病的必要事件。此外，p38有丝分裂原活化蛋白（MAP）激酶，一种已知的内皮细胞凋亡介质，在对MV损伤模式的反应中被激活。然而，p38 MAP激酶参与介导VALI发展和严重程度的下游效应物尚不清楚。p38 MAP激酶及其下游效应物mapk激活的蛋白激酶MK2 （MK2）的激活导致小热休克蛋白27 （HSP27）的磷酸化，HSP27是一种已知的细胞凋亡调节因子。此外，HSP25 （HSP27的小鼠同源物）的磷酸化与HVT MV介导的细胞凋亡和肺水肿相关。然而，MK2或HSP25促进VALI发展的具体机制尚不清楚。本研究将通过体外机械应力模型和建立野生型和MK2-/-小鼠的小鼠VALI模型，验证MK2介导的HSP27磷酸化对促进HVT MV介导的细胞凋亡和由此产生的肺水肿至关重要。本应用的具体目的是：1)明确MK2在体外促进机械应力诱导的细胞凋亡中的作用；2)明确HSP25/27磷酸化在体外机械应力诱导的细胞凋亡中的作用；3)确定HSP25/27磷酸化在HVT MV介导的细胞凋亡和由此产生的肺血管通透性中的作用。相关性（见说明书）：机械通气虽然是许多疾病治疗的基石，但有可能加剧和引起新发肺损伤。我们已经确定了与机械通气损伤介导相关的途径和潜在机制。我们希望进一步的了解将有助于确定新的治疗靶点。（摘要结束）

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)