Mechanisms of Fever-Enhanced Acute Lung Injury

描述（由申请人提供）：急性肺损伤（ALI）是危重患者常见的，通常是致命的并发症。我们已经做出了新的观察，发热范围热疗（FRH）通过大大增加中性粒细胞（pmn）向肺的募集而加剧了ALI。通过测量气管内IL-8对跨肺泡PMN募集的响应，我们证明小鼠暴露于FRH 16-24小时后，IL-8定向的跨肺泡PMN募集增加了10-23倍。FRH的启动效应持续48小时，并被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可能对PMN和肺血管系统都有启动作用。我们的初步结果表明，小鼠暴露于FRH会增加肺（连接粘附分子- a）和循环白细胞（CD18）中这些分子的mRNA水平。假设：我们提出FRH修饰内皮细胞和pmn以增加TEM的能力。我们假设p38和ERK的核心作用，关键粘附分子表达的调节，内皮细胞和PMN细胞骨架的修饰。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这一过程理解的空白。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，FRH通过这些分子事件增加了跨肺泡PMN募集的能力，重点关注p38和erk依赖基因的激活。相关性：在危重患者中很难实现退热，而体力/环境热疗通常是不可避免的。消融热既可以消除其有益的影响，也可以消除其有害的影响。更好地了解其分子机制将使我们能够有选择地阻断发烧/热疗的有害影响，并利用其有益影响。公共卫生相关性。在发烧或中暑时暴露在升高的体温下会改变血管和白细胞，从而增加白细胞从血液到肺部的运动。在感染期间，这种效果可以帮助消除细菌，但它也可能导致严重的肺损伤。由于退烧既可以消除它的有益影响，也可以消除它的有害影响，更好地了解高温是如何引起这些变化的，将使我们有选择地阻止发烧的有害影响。同样的知识将帮助我们开发更好的疗法来预防中暑并发症，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.