Mechanisms of Fever-Enhanced Acute Lung Injury

描述（由申请人提供）：急性肺损伤（ALI）是危重病患者常见的，往往是致命的并发症。我们已经作出了新的观察，发热范围高温（FRH）加剧了急性肺损伤大大增加招聘的中性粒细胞（PMNs）的肺。通过测量经肺泡的PMN募集对肺内IL-8的反应，我们证明了将小鼠暴露于FRH 16-24小时增加了随后的IL-8指导的经肺泡的PMN募集10-23倍。FRH的促发作用可持续48 h以上，并可被ERK和p38抑制剂阻断。使用一种新的过继性PMN转移技术，我们发现，FRH可能会对PMN和肺血管产生启动效应。我们的初步结果表明，暴露于FRH小鼠增加这些分子在肺（连接粘附分子-A）和循环白细胞（CD 18）的mRNA水平。假设：我们认为FRH通过修饰内皮细胞和中性粒细胞来增加TEM的能力。我们假设p38和ERK，调节关键的粘附分子的表达，并修改内皮细胞和中性粒细胞骨架的核心作用。具体目的：这些研究的总体目标是了解FRH增强PMN依赖性ALI的机制。在目标1中，我们将使用我们的体内跨肺泡PMN募集模型来填补我们对该过程的理解中的空白。在目标2和3中，我们将使用体外和体内模型来定义内皮细胞和PMN中的分子事件，通过FRH增加跨肺泡PMN募集的能力，重点是p38和ERK依赖的基因激活。相关性：在重症患者中很难实现退热，而且劳力性/环境性高热通常不可避免。发烧可以消除它的有益影响以及有害影响。更好地了解其分子机制将使我们能够选择性地阻断发热/高热的有害影响，并利用有益的影响。公共卫生相关性。暴露于发热或中暑期间发生的升高的体温改变血管和白色血细胞，以增加白色血细胞从血液到肺的运动。在感染期间，这种作用可以帮助消除细菌，但也可能导致严重的肺损伤。由于阻断发烧可能会消除其有益的影响以及有害的影响，更好地了解高温如何引起这些变化将使我们能够选择性地阻断发烧的有害影响。同样的知识将帮助我们开发更好的疗法，以预防中暑并发症，这是一个日益严重的全球健康问题。

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a common, often lethal, complication in the critically ill. We have made the novel observation that febrile range hyperthermia (FRH) exacerbates ALI by greatly increasing recruitment of neutrophils (PMNs) to the lung. By measuring trans-alveolar PMN recruitment in response to intratracheal IL-8, we demonstrated that exposing mice to FRH for 16-24 h increased subsequent IL-8-directed trans-alveolar PMN recruitment 10-23-fold. The priming effect of FRH lasted for >48h and was blocked by inhibitors of ERK and p38. Using a novel adoptive PMN transfer technique, we showed that FRH likely exerts priming effects on both PMNs and the pulmonary vasculature. Our preliminary results demonstrate that exposing mice to FRH increases mRNA levels for some of these molecules in lung (junctional adhesion molecule-A) and circulating leukocytes (CD18). HYPOTHESIS: We propose that FRH modifies endothelium and PMNs to increase CAPACITY for TEM. We postulate a central role for p38 and ERK, regulation of critical adhesion molecule expression, and modification of endothelial and PMN cytoskeleton. SPECIFIC AIMS: The overall objective of these studies is to understand the mechanisms by which FRH augments PMN-dependent ALI. In aim 1, we will use our in vivo trans-alveolar PMN recruitment model to fill in gaps in our understanding of the process. In aims 2 and 3, we will use in vitro and in vivo models to define the molecular events in endothelium and PMNs through which FRH increases CAPACITY for trans-alveolar PMN recruitment, focusing on p38- and ERK-dependent gene activation. RELEVANCE: Antipyresis is difficult to achieve in the critically ill and exertional/environmental hyperthermia is often unavoidable. Ablating fever may eliminate its beneficial as well as its harmful effects. A better understanding of its molecular mechanisms will allow us to selectively block the harmful effects of fever/hyperthermia and exploit the beneficial effects. PUBLIC HEALTH RELEVANCE. Exposure to elevated body temperatures as occurs during fever or heat stroke changes the blood vessels and white blood cells to increase movement of white blood cells from the blood to the lung. During infections this effect can help eliminate bacteria, but it can also cause severe lung injury. Since blocking fever may eliminate its beneficial as well as its harmful effects, a better understanding of how high temperatures cause these changes will allow us to selectively block the harmful effects of fever. The same knowledge will help us develop better therapies to prevent the complications of heat stroke, a growing global health problem.