Role of MAP Kinase Signaling in Ventilator-Associated Lung Injury

描述（由申请方提供）：急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是重症监护室发病率和死亡率的重要原因。对机械通气有害作用的认识已导致对呼吸机相关肺损伤（VALI）中观察到的急性炎症和血管通透性增强所涉及的途径的兴趣日益增加。低潮气量肺策略仍然是ALI/VALI唯一有效的支持性治疗方法。因此，需要特异性靶向涉及ALI/VALI的屏障破坏和急性炎症的机制的新疗法。损伤的一个潜在机制是p38-MK2-HSP 27途径的激活，导致肌动蛋白细胞骨架重排和导致的内皮屏障功能障碍。p38 MAP激酶响应于多种刺激而被激活，其中许多存在于ALI/VALI患者中，即，缺氧、细胞因子，特别是机械应力。为此，需要进一步研究p38 MAP激酶及其下游效应物在VALI中的作用。在这项研究中，我们将首先研究机械应力对p38-MK 2-HSP 27通路的表达和激活的影响，无论是在小鼠VALI模型和内皮细胞拉伸模型。接下来，我们将探讨p38-MK2-HSP 27通路的药理学和遗传学操作对内皮细胞周期性牵张的影响。最后，我们将把体内p38 MAP激酶通路的操作与VALI的测量相关联。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发肺损伤。我们已经确定了一个相关的途径，在介导损伤，由于机械通气。我们希望对这一关键途径的进一步了解将有助于确定新的治疗靶点。

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.