Liver-Dependent Lung Remodeling and Pneumonia Susceptibility During Endotoxemia

项目摘要/摘要 肺炎是全球传染病死亡的主要原因，也是导致全球死亡的最大原因之一 世界范围内的疾病负担。它也是败血症的主要原因，这反过来又使患者容易患上 肺部和其他部位的继发性感染。事实上，患有败血症、创伤或肺外疾病的患者 并发症极易感染医院获得性肺炎。这两种疾病都越来越为公众所知 有限治疗带来的健康问题。由于肺炎和败血症的综合性质，认识到 控制全身炎症后肺炎易感性的肺内外途径 或者，损伤可能会暴露出靶向干预的保护性信号中枢。肝脏急性期反应 (Apr)由肺炎和败血症激活，是一种协调反应，导致大量血液蛋白。 与疾病严重程度和调节宿主结局相关的变化，尽管在某种程度上仍然存在 投机性的。我们已经证明，肺炎期间强劲的APR是由肝脏激活 转录因子STAT3和RELA，当这两个因子中的一个或两个被消除时，APR就会减少 或完全消融。在早期的一项研究中，我们模拟了肺炎的易感性条件 气管内滴注内毒素血症小鼠在脓毒症/全身炎症中的作用 细菌的数量。这些研究显示，缺乏肝细胞的小鼠的肺炎结局显著恶化。 在相同条件下，将STAT3(HepSTAT3-/-)与产仔对照进行比较。而肝脏的机制- 派生保护仍然不清楚，我们先前和初步的结果一起表明两者都参与了 肺免疫状况中的细胞和先天体液变化。这些变化包括空域 巨噬细胞的功能以及依赖肝脏的肺转录组和空泡蛋白质组的重塑。这个 后者对应于肝脏合成减少和凝血蛋白向肺泡室输送 HepSTAT3-/-小鼠。基于这些发现，我们提出了STAT3依赖的肝脏的中心假设 激活通过重新编程肺巨噬细胞和调度凝血来限制肺炎易感性 蛋白质进入受感染的空间。AIM 1旨在检验STAT3依赖于肝脏活动的假设 在内毒素血症和肺炎期间重塑肺巨噬细胞，而目标2的目标是测试 肝源性凝血蛋白增强肺内细菌杀灭和改善肺炎的假说 结果。这些研究将为研究连接肝脏的生物途径提供重要的见解。 激活与肺炎易感性，可能揭示对脆弱患者的有针对性的临床干预 人口。

Project Summary/Abstract Pneumonia is the leading global cause of infectious disease deaths and contributes to one of the greatest disease burdens worldwide. It is also the leading cause of sepsis, which in turn predisposes patients to secondary infections in the lungs and elsewhere. Indeed, patients with sepsis, trauma, or extra-pulmonary complications are exquisitely vulnerable to hospital-acquired pneumonias. Both diseases are growing public health concerns with limited treatments. Due to the integrated nature of pneumonia and sepsis, understanding intra- and extra-pulmonary pathways controlling pneumonia susceptibility in the wake of systemic inflammation or injury may reveal protective signaling hubs for targeted interventions. The hepatic acute phase response (APR), activated by both pneumonia and sepsis, is a coordinated response resulting in numerous blood protein changes that correlate with disease severity and modulate host outcome, albeit in ways that remain somewhat speculative. We have shown that a robust APR during pneumonia is coordinated by liver activation of the transcription factors STAT3 and RelA, and when one or both of these factors are eliminated, the APR is diminished or completely ablated, respectively. In an earlier study, we modeled the conditions of pneumonia susceptibility during sepsis/systemic inflammation by pre-challenging mice with endotoxemia prior to an intratracheal instillation of bacteria. These studies revealed substantially worsened pneumonia outcomes in mice lacking hepatocyte STAT3 (hepSTAT3-/-) compared to littermate controls under the same conditions. While mechanisms of liver- derived protection remain unclear, our prior and preliminary results together suggest the involvement of both cellular and innate humoral changes in the immune landscape of the lung. Such changes include airspace macrophage function as well as liver dependent remodeling of the lung transcriptome and airspace proteome. The latter corresponds with reduced hepatic synthesis and delivery of coagulation proteins to the alveolar compartment of hepSTAT3-/- mice. Based on these findings, we propose the central hypothesis that STAT3-dependent liver activation limits pneumonia susceptibility by reprogramming lung macrophages and dispatching coagulation proteins to infected airspaces. Aim 1 is designed to test the hypothesis that STAT3-dependent liver-activity remodels lung macrophages during endotoxemia followed by pneumonia, whereas the goal of aim 2 is to test the hypothesis that liver-derived coagulation proteins fortifies intrapulmonary bacterial killing and improves pneumonia outcome. These studies will provide important insights regarding the biological pathways connecting liver activation and pneumonia susceptibility, possibly revealing targetable clinical interventions for vulnerable patient populations.