Characterization of Atypical p38 signaling in Acute Lung Injury

丝裂原活化蛋白激酶（MAPK）p38是血管破裂/水肿的关键介质， 炎症信号传导与 急性肺损伤（ALI）、急性呼吸窘迫综合征（ARDS）。 然而，由于p38在生理上普遍存在的作用，p38定向治疗在临床上失败了 所有组织中的活性。因此，迫切需要探索有选择地监管的替代机制， 病理性p38信号通路。一个未充分研究的非典型p38激活途径最近被发现， 发现通过p38与接头的直接相互作用， 蛋白TAB 1，独立于经典的p38激活MKK 3/6。这一未被充分探索的途径的作用 在肺功能中的作用尚未研究，这代表了我们分子知识的一个主要空白 ALI/ARDS。 已知P38信号传导调节炎性细胞因子表达、血管功能障碍、巨噬细胞和 中性粒细胞活化和募集，增强肺损伤的进展。非典型p38信号转导 在脉管系统中快速诱导炎性细胞因子表达的产生和血管渗漏， 巨噬细胞募集这些研究的目的是了解非典型MAPK对细胞的生理影响， p38信号在LPS诱导的急性肺损伤早期肺血管中的表达， 造成肺损伤。 我们的核心假设 破裂，肺泡损伤， 非典型p38激活在血管增生中起关键作用， 和急性肺损伤中的肺部炎症反应。从这个 假设我们提出两个具体的目标：1）表征非典型p38信号转导对肺动脉粥样硬化的贡献， 水肿/血管失调，2）表征ALI中的非典型p38促炎反应。我们还将使用 在全身性TAB 1-KI小鼠与野生型小鼠中使用脂多糖（LPS）的急性肺损伤（ALI）模型 小鼠和可阻断非典型p38信号传导的细胞穿透抑制剂肽。我们预测封锁 非典型p38信号转导的表达将显著减轻体内肺水肿，并在肺水肿中发挥关键作用。 体外和体内内皮屏障失调。此外，我们预测这些研究将证明， 非典型p38信号在细胞因子表达中的明确作用，导致中性粒细胞的激活和募集 和巨噬细胞。重要的是，这些研究将是第一个确定非典型p38信号传导在急性胰腺炎中的作用的研究。 为进一步深入研究非典型肺损伤提供了必要的基础证据 p38信号转导。此外，这些研究将证明选择性地治疗未来的治疗潜力。 抑制血管和肺部炎症性疾病中的非典型p38信号传导。

Mitogen-activated protein kinase (MAPK) p38 is a critical mediator of vascular disruption/edema and inflammatory signaling associated with acute lung injury (ALI), acute respiratory distress syndrome (ARDS). However, p38 directed therapeutics have failed in the clinic due to the physiologically ubiquitous role of p38 activity in all tissues. Thus, there is an essential need to explore alternative mechanisms that selectively regulate pathological p38 signaling pathways. An understudied atypical p38 activation pathway has recently been discovered that selectively regulates pathological signaling induced via a direct p38 interaction with the adaptor protein TAB1, independent from classical p38 activation by MKK3/6. The role of this underexplored pathway in pulmonary function has not been investigated, representing a major gap in our molecular knowledge of ALI/ARDS. P38 signaling is known to regulate inflammatory cytokine expression, vascular dysfunction, macrophage and neutrophil activation and recruitment, enhancing the progression of pulmonary damage. Atypical p38 signaling in the vasculature rapidly induces production of inflammatory cytokine expression and blood vessel leakage, and macrophage recruitment. The goal of these studies is to understand the physiological impact that atypical MAPK p38 signaling has in pulmonary vasculature during the initial stages of LPS induced acute lung injury, and its contribution to pulmonary damage. Our central hypothesis disruption, alveolar damage, is that atypical p38 activation plays a key role in propagating vascular and pulmonary inflammatory responses in acute lung injury. From this hypothesis we propose two specific aims: 1) Characterize the contribution of atypical p38 signaling to pulmonary edema/vascular dysregulation, 2) Characterize atypical p38 pro-inflammatory responses in ALI. We will also use an acute lung injury (ALI) model using lipopolysaccharide (LPS) in a systemic TAB1-KI mouse verses wild-type mouse and a cell-penetrating inhibitor peptide which can block atypical p38 signaling. We predict that blockade of atypical p38 signaling will significantly reduce pulmonary edema in vivo and establish a critical role in endothelial barrier dysregulation in vitro and in vivo. Furthermore, we predict that these studies will demonstrate a clear role for atypical p38 signaling in cytokine expression, leading to activation and recruitment of neutrophils and macrophages. Critically, these studies will be the first to define the role of atypical p38 signaling in acute lung injury and provide essential foundational evidence for further more detailed studies into pulmonary atypical p38 signaling. Furthermore, these studies will demonstrate the future therapeutic potential for selectively inhibiting atypical p38 signaling in vascular and pulmonary inflammatory diseases.