Role of MAP Kinase Signaling in Ventilator-Associated Lung Injury

描述(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率和死亡率的重要原因。随着对机械通气有害作用的认识，人们对呼吸机相关性肺损伤(VALI)的急性炎症和血管通透性增加所涉及的通路越来越感兴趣。低潮气量肺策略仍然是ALI/VALI唯一被证实有效的支持性治疗方法。因此，需要针对ALI/VALI屏障破坏和急性炎症机制的新疗法。一个潜在的损伤机制是激活p38-MK2-HSP27通路，导致肌动蛋白细胞骨架重排，导致内皮屏障功能障碍。P38 MAP Kinase在多种刺激下被激活，其中许多刺激存在于ALI/VALI患者中，即缺氧、细胞因子，特别是机械应激。为此，有必要进一步研究p38MAPK及其下游效应因子在VALI中的作用。在这项研究中，我们将初步研究机械应激对小鼠VALI模型和内皮细胞拉伸模型中p38-MK2-HSP27途径表达和激活的影响。接下来，我们将探索药物和遗传操作对p38-MK2-HSP27通路的影响，以响应内皮细胞的周期性拉伸。最后，我们将在体内将p38MAP激酶通路的操纵与VALI的测量相关联。机械通气虽然是治疗许多疾病的基石，但也有可能加重和造成从头开始的肺损伤。我们已经确定了一条与机械通气所致损伤的中介相关的途径。我们希望对这一重要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.