Role of MAP Kinase Signaling in Ventilator-Associated Lung Injury

MAP 激酶信号传导在呼吸机相关肺损伤中的作用

• 批准号: 7485792
• 负责人: Mahendra Damarla
• 金额: $ 5.29万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-13 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485792
• 关键词: Actins; Acute; Acute Lung Injury; Blood Vessels; Brain; Capillary Permeability; Complex; Cytoskeletal Modeling; Cytoskeleton; DNA Sequence Rearrangement; Data; Disease; Disruption; Edema; Endothelial Cells; Functional disorder; HSPB1 gene; Heat shock proteins; Homologous Gene; Hypoxia; In Vitro; Incidence; Inflammation; Injury; Intensive Care Units; Investigation; Laboratories; Lung; MAP Kinase Gene; MAPK14 gene; Measures; Mechanical Stress; Mechanical ventilation; Mechanics; Mediating; Mitogen-Activated Protein Kinases; Modeling; Morbidity - disease rate; Mus; Newborn Respiratory Distress Syndrome; Pathologic; Pathway interactions; Patients; Permeability; Personal Satisfaction; Play; Protein Kinase; Respiratory System; Role; Sepsis; Signal Pathway; Signal Transduction; Stimulus; Stress Fibers; Stretching; Syndrome; Testing; Tidal Volume; Tissues; Vascular Permeabilities; Ventilator; cytokine; genetic manipulation; human MAPK14 protein; in vitro Model; in vivo; insight; interest; kidney vascular structure; lung injury; mitogen-activated protein kinase p38; mortality; novel; novel therapeutics; response; therapeutic target; vascular bed

DESCRIPTION (provided by applicant): Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are significant causes of morbidity and mortality in the intensive care unit. The recognition of the deleterious effects of mechanical ventilation has led to increasing interest in the pathways involved in the acute inflammation and enhanced 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 and acute inflammation of ALI/VALI are needed. A potential mechanism of injury is the activation of the p38-MK2-HSP27 pathway leading to actin cytoskeletal rearrangement and resulting endothelial barrier dysfunction. p38 MAP Kinase is activated in response to multiple stimuli, many of which are present in patients with ALI/VALI, i.e., hypoxia, cytokines, and particularly mechanical stress. To this end, further investigation of the role of p38 MAP kinase and its downstream effectors in VALI is warranted. In this study, we will initially investigate the effects of mechanical stress on p38-MK2-HSP27 pathway expression and activation, both in a murine VALI model and an endothelial cell stretch model. Next, we will explore the effects of pharmacologic and genetic manipulation of the p38-MK2-HSP27 pathway in response to cyclic stretch in endothelial cells. Lastly, we will correlate the manipulation of the p38 MAP Kinase pathway in vivo to measures of VALI. 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 that is relevant in mediating injury due to mechanical ventilation. We hope that further insight into this crucial pathway will help identify novel therapeutic targets.

描述（由申请人提供）：急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是重症监护病房发病和死亡率的重大原因。机械通气的有害作用的识别导致人们对急性炎症中涉及的途径的兴趣增加，并在呼吸机相关的肺损伤（VALI）中观察到的血管通透性增强。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，需要专门针对涉及屏障破坏和急性ALI/VALI急性炎症的新疗法。损伤的潜在机制是p38-MK2-HSP27途径的激活，导致肌动蛋白细胞骨架重排和由此产生的内皮屏障功能障碍。 p38 MAP激酶是针对多种刺激而激活的，其中许多刺激存在于ALI/VALI的患者，即缺氧，细胞因子，尤其是机械胁迫中。为此，有必要进一步研究p38 MAP激酶及其下游效应子在Vali中的作用。在这项研究中，我们最初将在鼠瓦利模型和内皮细胞拉伸模型中研究机械应力对p38-MK2-HSP27途径表达和激活的影响。接下来，我们将探讨p38-MK2-HSP27途径的药理和遗传操纵的影响，以响应内皮细胞中的环状拉伸。最后，我们将将体内p38 MAP激酶途径的操纵与vali的量度相关联。机械通气虽然是许多疾病的治疗基石，但仍有可能加剧并引起从头肺损伤。我们已经确定了一条与机械通气引起的损伤相关的途径。我们希望对这一关键途径的进一步了解将有助于确定新颖的治疗靶标。