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、通常是致命的并发症。我们发现，热程热疗(FRH)通过显著增加中性粒细胞(PMN)向肺内募集而加重ALI。通过测量气管内IL-8对PMN跨肺泡募集的反应，我们证明，暴露于FRH 16-24小时使随后IL-8导向的PMN跨肺泡募集增加10-23倍。FRH的启动作用可持续48h，并可被ERK和p38抑制剂阻断。使用一种新的过继PMN转移技术，我们发现FRH可能在PMN和肺血管系统上都起到启动作用。我们的初步结果表明，暴露在FRH中的小鼠增加了肺(连接黏附分子-A)和循环白细胞(CD18)中这些分子中的一些分子的mRNA水平。假设：我们认为FRH可以改变内皮细胞和中性粒细胞，以增加对瞬变电磁的能力。我们推测p38和ERK在调节关键黏附分子的表达，以及内皮和PMN细胞骨架的修饰中起着中心作用。具体目标：这些研究的总体目标是了解FRH增加PMN依赖的ALI的机制。在目标1中，我们将使用我们的体内跨肺泡PMN招募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和PMN中的分子事件，FRH通过这些事件增加跨肺泡PMN的募集能力，重点是p38和ERK依赖的基因激活。相关性：危重病人很难退烧，体力/环境高温往往是不可避免的。消融发烧可以消除其有益和有害的影响。更好地了解其分子机制将使我们能够有选择地阻断发热/高热的有害影响，并利用其有益的影响。与公共卫生相关。在发烧或中暑期间暴露在较高的体温下会改变血管和白细胞，以增加白细胞从血液到肺的移动。在感染期间，这种效应可以帮助消除细菌，但也可能导致严重的肺损伤。由于阻烧可以消除其有益和有害的影响，更好地了解高温是如何导致这些变化的，将使我们能够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治疗方法，以预防中暑的并发症，中暑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.