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

凋亡诱导的呼吸机相关肺损伤中的 MAP 激酶信号转导

基本信息

批准号：
8496607
负责人：
Mahendra Damarla
金额：
$ 15.96万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8496607
关键词：
Acute Lung Injury Apoptosis Apoptosis Regulator Apoptotic Blood Vessels Blood capillaries Cells Complex Data Development Disease Edema Endothelial Cells Enzymes Event Functional disorder Heat Shock Protein 27 Homologous Gene Hypoxia In Vitro Incidence Injury Instruction Lung MAP Kinase Gene MAPK14 gene Mechanical Stress Mechanical ventilation Mechanics Mediating Mediator of activation protein Mitogen-Activated Protein Kinases Modeling Molecular Molecular Chaperones Morbidity - disease rate Mus Pathogenesis Pathway interactions Permeability Phosphorylation Protein Kinase Pulmonary Edema Research Personnel Respiratory System Role Severities Signal Transduction Stress Stretching Supportive care Syndrome Testing Therapeutic Tidal Volume Tissues Vascular Permeabilities Ventilator capillary caspase-3 human MAPK14 protein in vivo insight interest lung injury mortality new therapeutic target novel pressure pulmonary vascular permeability response

项目摘要

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.

急性肺损伤（ALI）是一种毁灭性疾病，发病率和死亡率非常高，治疗方法有限选项.认识到机械通气（MV）的有害影响，治疗急性肺损伤，已导致越来越多的兴趣，在途径参与肺血管通透性在呼吸机相关肺损伤（VALI）中观察到。低潮气量肺策略仍然是唯一的 ALI/VALI的支持性治疗已证实有效。因此，新的疗法，将专门针对在阿利亚/ALI中需要涉及屏障破坏的机制。内皮细胞凋亡已经成为最近被认为是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的介质，响应于 MV的有害模式。然而，p38 MAP激酶的下游效应物参与介导了细胞凋亡， VALI的发展和严重程度仍然未知。p38 MAP激酶及其下游的激活效应MAPK激活的蛋白激酶MK2（MK2）导致小的热休克蛋白磷酸化 27（HSP 27），一种已知的细胞凋亡调节因子。此外，HSP 25的磷酸化（HSP 27的鼠同源物）与HVT MV介导的细胞凋亡和肺水肿相关。但具体 MK2或HSP 25促进VALI发展的机制尚不清楚。这项建议将检验MK2介导的HSP 27磷酸化对促进HVT MV至关重要的假设介导的细胞凋亡和由此产生的肺水肿，使用体外机械应力模型，在野生型和MK2-/-小鼠中建立VALI的鼠模型。本申请的具体目的是： 1)确定MK2在体外促进机械应力诱导的细胞凋亡中的作用; 2）确定MK2在体外促进机械应力诱导的细胞凋亡中的作用。 HSP 25/27磷酸化在体外机械应力诱导的细胞凋亡中的作用; HVT MV中HSP 25/27磷酸化介导的细胞凋亡和肺血管通透性 vivo. 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生肺损伤。我们已经确定了一种途径和潜在的机制，与调解机械通气造成的伤害有关。我们希望进一步的了解将有助于确定新的治疗目标