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：
8286945
负责人：
Mahendra Damarla
金额：
$ 16.09万
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/8286945
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，发病率很高，死亡率有限选项。对机械通气（MV）的有害影响的认识，主要支撑性 ALI的治疗已导致人们对参与肺血管通透性的途径的兴趣增加在呼吸机相关的肺损伤（VALI）中观察到。潮汐量低的肺策略仍然是唯一的具有可靠的功效的ALI/VALI的支持治疗。因此，将专门针对的新型疗法需要在ALIA/ALI中涉及屏障破坏的机制。内皮细胞凋亡一直是最近在Vali的早期发病机理中被认为是必要的事件。另外，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，以响应于 MV有害模式。但是，p38 MAP激酶的下游效应子涉及介导瓦利的发展和严重程度仍然未知。 p38 MAP激酶的激活及其下游效应子MAPK激活的蛋白激酶MK2（MK2）导致小热激蛋白的磷酸化 27（HSP27），已知的凋亡调节剂。另外，HSP25的磷酸化（HSP27的鼠同源物与HVT MV介导的凋亡和肺水肿相关。但是，具体 MK2或HSP25有助于Vali的发展的机制尚不清楚。这个建议将检验以下假设：MK2介导的Hsp27的磷酸化对于促进HVT MV至关重要使用体外机械应力模型和一个在野生型和MK2 - / - 小鼠中建立的瓦利鼠模型。本应用程序的具体目的是： 1）定义MK2在体外促进机械应力诱导的凋亡中的作用； 2）定义角色 HSP25/27在体外机械应力诱导的凋亡中的磷酸化； 3）确定 HSP25/27 HVT MV介导的凋亡中的磷酸化和由此导致的肺血管通透性体内。相关性（请参阅说明）：机械通气虽然是许多疾病的治疗的基石，但有可能加重并造成从头肺损伤。我们已经确定了一种途径和一种潜在机制与机械通气引起的损伤有关。我们希望进一步的见识将有助于确定小说治疗靶标。