Inducible epithelial resilience during pneumonia

摘要 肺炎是整个社会经济领域发病率和死亡率的主要原因。它也是世界上 急性呼吸窘迫综合征(ARDS)最常见的原因，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。后者对于以下方面至关重要 保持屏障的完整性，限制肺泡泛滥，但宿主机制保护微妙的气液 肺炎期间的相互作用仍然知之甚少。我们之前已经证明了IL-6家族细胞因子 白血病抑制因子(LIF)在限制感染所致急性肺损伤中的作用及其保护作用 属性似乎不会影响宿主免疫力。对生物信号有更全面的了解 这种细胞保护因子的上下游，目前尚不清楚，可能提供一种独特的和 在不影响抗菌防御的情况下决定组织动态平衡的途径的重要窗口。 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，作为一种诱导弹性的机制。初步结果还表明，这种反应是 巨噬细胞介导的，并可能涉及依赖LIF的细胞保护性转录辅助性改变。 激活剂是相关蛋白(YAP)，以及低密度脂蛋白受体-1(LOX-1)的调节， 这可能会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 在肺炎肺中由巨噬细胞依赖的旁分泌LIF轴维持，促进组织 恢复力。这一假设将通过追求以下三个目标来检验：目标1)检验以下假设 肺上皮细胞中的LIFRβ信号可预防肺炎期间的急性肺损伤；目的2)验证这一假设 巨噬细胞-上皮细胞通讯启动LIF介导的组织保护回路；和目的3) 验证LOX-1诱导上皮细胞对肺炎肺损伤敏感的假设，并被反驳 通过激光诱导因子增强组织弹性。旨在解决这些目标的研究将在体内使用补充 以及体外策略，以揭示肺部感染环境中组织保护的新途径。我们 预期这些发现将被用于开发新的患者临床干预措施 有肺炎和ARDS的或有患肺炎和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.