Liver-derived protection during pneumonia and sepsis

摘要 肺炎和败血症是紧密联系的，每一个都代表着一个主要的公共卫生问题， 这大大增加了另一种情况发生的可能性。然而，引导这一点的主机机制 危险的相互作用仍然是推测性的。急性期反应是两种肺炎的共同特征 和脓毒症，涉及肝脏转录组的强烈重塑，随后动员大量的 肝源性急性期蛋白，其中几种是已知的疾病严重程度的临床生物标志物。净 这些综合的急性时相变化的生理意义才刚刚开始被理解。我们 最近表明，肺炎引起了一种强烈的急性期反应， 依赖于转录因子NF-κB RelA和STAT 3的肝细胞表达。使用肝细胞- 针对小鼠模型，我们的初步研究暗示肝脏作为一个看门人， 败血症或肺炎期间的感染，减少了一个会促进另一个的可能性。我们特别 现在有证据表明：1）STAT 3依赖性肝脏对内毒素血症的反应可预防肺炎 易感性，与铁调节急性期蛋白的表达相关;和2）RelA依赖性肝脏 肺炎期间的反应可防止脓毒症结局，包括肝衰竭和菌血症。这里我们 提出了核心假设，即肝细胞的转录反应对于限制有害的 肺炎和败血症之间的相互作用。这一假设将通过以下三个方面进行检验 目的：1）检验肝细胞STAT 3激活对抗脓毒症诱导的肺炎的假设 通过促进铁的戒断和肺粘膜防御的易感性;目的2）测试假设， 肝细胞RelA激活通过防止程序性细胞死亡对抗肺炎诱导的脓毒症，器官 目的3）检验STAT 3和RelA各自对人类免疫系统的维持和维持是必需的这一假设。 肝细胞以引发指导肺泡巨噬细胞应答的急性期基因程序。设计的研究 为了实现这些目标，将使用多学科方法来全面确定 在肺炎和脓毒症的界面处的肝源性保护的基础。这些调查将是第一次 以这种能力直接询问肝功能，可能揭示临床指标的重要决定因素。 肺炎或脓毒症患者的结局。

Abstract Pneumonia and sepsis are integrally linked, each representing a major public health concern, and each significantly increasing the likelihood that the other will occur. However, the host mechanisms guiding this dangerous interaction remain speculative. The acute phase response is a common feature of both pneumonia and sepsis, involving robust remodeling of the hepatic transcriptome followed by mobilization of numerous liver-derived acute phase proteins, several of which are known clinical biomarkers of disease severity. The net physiological significance of these integrated acute phase changes is only beginning to be understood. We recently showed that pneumonia elicits a robust acute phase response that is functionally relevant and highly dependent on hepatocyte expression of the transcription factors NF-κB RelA and STAT3. Using hepatocyte- targeted mouse models, our preliminary studies implicate the liver as a gatekeeper that compartmentalizes infection during sepsis or pneumonia, reducing the likelihood that one will promote the other. Specifically, we now have evidence that: 1) STAT3-dependent liver responses to endotoxemia protect against pneumonia susceptibility, associated with expression of iron-regulating acute phase proteins; and 2) RelA-dependent liver responses during pneumonia protect against sepsis outcomes, including liver failure and bacteremia. Here we propose the central hypothesis that hepatocyte transcriptional responses are critical for limiting the deleterious interactions between pneumonia and sepsis. This hypothesis will be tested by pursuing the following three aims: Aim 1) Test the hypothesis that hepatocyte STAT3 activation counters sepsis-induced pneumonia susceptibility by promoting iron withdrawal and lung mucosal defense; Aim 2) Test the hypothesis that hepatocyte RelA activation counters pneumonia-induced sepsis by preventing programmed cell death, organ failure, and bacteremia; and Aim 3) Test the hypothesis that STAT3 and RelA are each essential for human hepatocytes to elicit acute phase gene programs that direct alveolar macrophage responses. Studies designed to address these aims will use a multidisciplinary approach to comprehensively determine the mechanistic basis of liver-derived protection at the interface of pneumonia and sepsis. These investigations will be the first to directly interrogate liver function in this capacity, possibly revealing important determinants of clinical outcome in patients with pneumonia or sepsis.