Inducible epithelial resilience during pneumonia

摘要 肺炎是整个社会经济范围内发病率和死亡率的主要原因。也是 急性呼吸窘迫综合征（ARDS）的最常见原因，在很大程度上是由于有害的失衡 促进抗菌素耐药性和组织弹性的生物途径。后者是必不可少的， 维持屏障的完整性和限制肺泡洪水，但主机机制保护微妙的气液 肺炎期间的界面仍然知之甚少。我们先前已经证明IL-6家族细胞因子 白血病抑制因子（LIF）对于限制感染引起的急性肺损伤至关重要， 这些特性似乎不影响宿主免疫力。更全面地了解生物信号 目前尚不清楚的这种细胞保护因子的上游和下游，可能提供了独特的， 这是一个重要的窗口，可以进入决定组织稳态而不影响抗菌防御的途径。 我们发表的和初步的结果表明，肺上皮细胞既是LIF的来源，也是LIF的靶点。 肺炎，作为一种诱导性恢复机制。初步结果还表明，这种反应是 巨噬细胞介导的，它可能涉及LIF依赖性的变化，在细胞保护性转录共 激活因子Yes相关蛋白（雅普），以及低密度脂蛋白受体-1（LOX-1）的调节， 它可以促进损伤和细胞死亡。在这里，我们提出了一个中心假设，即上皮完整性是 通过巨噬细胞依赖性旁分泌LIF轴维持， resilience.这个假设将通过追求以下3个目标进行测试：目标1）测试假设， 肺上皮细胞LIFRβ信号通路可预防肺炎期间的急性肺损伤;目的2）检验假设 巨噬细胞-上皮细胞通讯启动由LIF介导的组织保护回路;以及目的3） 验证LOX-1诱导使上皮细胞对肺炎性肺损伤敏感， 通过LIF来增强组织弹性。旨在解决这些目标的研究将采用补充体内 和离体策略，以揭示肺部感染背景下组织保护的新途径。我们 预计这些发现将用于开发新的临床干预措施， 患有肺炎和ARDS或有患肺炎和ARDS的风险。

Abstract Pneumonia is a leading cause of morbidity and mortality across the socioeconomic spectrum. It is also the most frequent cause of acute respiratory distress syndrome (ARDS), due in large part to a harmful imbalance of biological pathways promoting antimicrobial resistance and tissue resilience. The latter is essential for maintaining barrier integrity and limiting alveolar flooding, but host mechanisms protecting the delicate air-liquid interface during pneumonia remain poorly understood. We have previously shown that the IL-6 family cytokine leukemia inhibitory factor (LIF) is critical for limiting acute lung injury in response to infection, and its protective properties do not appear to influence host immunity. A more complete understanding of the biological signals up- and downstream of this cytoprotective factor, which are currently unclear, may provide a unique and important window into pathways that dictate tissue homeostasis without compromising antimicrobial defense. Our published and preliminary results suggest that lung epithelium is both the source and target of LIF during pneumonia, serving as a mechanism of inducible resilience. Initial results also suggest that this response is macrophage-mediated, and that it may involve LIF-dependent changes in the cytoprotective transcriptional co- activator Yes-associated protein (YAP), as well as regulation of the low-density lipoprotein receptor-1 (LOX-1), which can promote injury and cell death. Here we propose the central hypothesis that epithelial integrity is maintained in pneumonic lungs by a macrophage-dependent paracrine LIF axis that promotes tissue resilience. This hypothesis will be tested by pursuing the following 3 aims: Aim 1) Test the hypothesis that LIFRβ signaling in lung epithelium prevents acute lung injury during pneumonia; Aim 2) Test the hypothesis that macrophage-epithelial communication initiates the tissue protective circuit mediated by LIF; and Aim 3) Test the hypothesis that LOX-1 induction sensitizes epithelial cells to pneumonic lung injury, and is countered by LIF to fortify tissue resilience. Studies designed to address these aims will employ complementary in vivo and ex vivo strategies to reveal novel pathways of tissue protection in the setting of lung infection. We anticipate that these findings will be leveraged for the development of novel clinical interventions in patients with or at risk for pneumonia and ARDS.