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：
7713110
负责人：
Mahendra Damarla
金额：
$ 16.12万
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/7713110
关键词：
Acute 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 Mitogens Modeling Molecular Molecular Chaperones Morbidity - disease rate Mus Pathogenesis Pathway interactions Permeability Phosphorylation Protein Kinase Proteins Pulmonary Edema Research Personnel Respiratory System Role Severities Signal Transduction Stress Stretching Supportive care Syndrome Testing Therapeutic Tidal Volume Tissues Vascular Permeabilities Ventilator abstracting 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

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)

描述（由申请人提供）：急性肺损伤（ALI）是一种毁灭性的疾病，发病率和死亡率很高，治疗选择有限。对ALI的主要支持治疗机械通气（MV）的有害作用的识别导致人们对与呼吸机相关的肺损伤（VALI）中有关肺血管通透性涉及的途径的兴趣日益增加。潮汐量低的肺策略仍然是对ALI/VALI具有可靠功效的唯一支持治疗。因此，需要特异性靶向涉及屏障破坏的新型疗法。在瓦利的早期发病机理中，最近已将内皮细胞凋亡视为必要的事件。此外，p38有丝分裂原活化蛋白（MAP）激酶是一种已知的内皮细胞凋亡介质，以响应MV的伤害模式而激活。但是，参与介导瓦利的发育和严重程度的p38 MAP激酶的下游效应子仍然未知。 p38 MAP激酶的激活及其下游效应子MAPK激活的蛋白激酶MK2（MK2）导致小热休克蛋白27（HSP27）的磷酸化，这是已知的凋亡调节剂。此外，Hsp25（HSP27的鼠同源物）的磷酸化与HVT MV介导的凋亡和肺水肿相关。但是，MK2或HSP25促进Vali的发展的特定机制是未知的。该提案将检验以下假设：HSP27的MK2介导的磷酸化对于促进HVT MV介导的凋亡至关重要，并使用体外机械应力模型以及野生型和Mk2 - / - 小鼠的Vali熟鼠模型使用体外机械应力模型和肺含量模型至关重要。该应用的具体目的是：1）定义MK2在促进机械应力诱导的体外凋亡中的作用； 2）定义Hsp25/27磷酸化在机械应力诱导的体外凋亡中的作用； 3）确定Hsp25/27磷酸化在HVT MV介导的凋亡中的作用和体内肺血管通透性的作用。相关性（请参阅说明）：机械通气，尽管许多疾病的治疗基石具有加剧并引起从头肺损伤的潜力。我们已经确定了一种途径和潜在机制，该途径与机械通气引起的损伤有关。我们希望进一步的见解将有助于确定新颖的治疗靶标。（抽象的结尾）