LOX-1 as a protective countermeasure in response to lung infection

摘要 肺炎是全世界发病率和死亡率的主要原因，很大程度上是由于急性肺炎的发病。 呼吸窘迫综合征(ARDS)，没有更大的来源。生物界的失衡 控制免疫和组织完整性的过程增加了肺部感染进展为 肺炎，要求更好地了解何时、何地以及如何整合宿主信号以传递 保护。在这里，我们提出了清道夫受体凝集素样氧化低密度脂蛋白受体-1 (LOX-1)作为肺炎肺部炎症形成的调节节点。虽然这种受体有很好的- 在动脉粥样硬化患者中促进血管损伤的既定作用，其在肺中的功能是 未知。我们在小鼠和人类身上的初步结果表明，LOX-1在 肺炎肺。此外，我们的小鼠研究表明，LOX-1在空域隔间，特别是 它源于造血细胞，抑制了受感染肺的免疫病理。这与 LOX-1在心血管疾病中的有害作用，表明肺泡环境是 依赖LOX-1的组织强化。尽管LOX-1从未在肺的背景下被研究过 感染，我们假设其通过肺泡巨噬细胞和中性粒细胞表达作为一种对策 抑制肺炎引起的炎症，保持组织完整性。因此，我们将测试中央 假设空气中髓系细胞上的LOX-1增强了对肺部感染的组织保护。这 将通过追求以下3个目标来解决：目标1)检验假设的造血细胞亚群 在受感染的肺中显著促进LOX-1驱动的组织保护；目的2)检验假设 LOX-1促进肺泡巨噬细胞吞噬和复极化以限制免疫病理 肺炎；以及目的3)检验LOX-1引导肺泡中性粒细胞向MDSC样细胞转化的假设 通过改变脂质处理和抗炎反馈，对抗感染引起的损伤。我们的 拟议的研究将利用体内和体外的互补方法，以揭示基本的 肺炎期间组织动态平衡的生物学机制，为新的临床干预措施铺平道路 在患有这种疾病或有这种疾病风险的患者中。

Abstract Pneumonia is a leading cause of morbidity and mortality worldwide, due in large part to the onset of acute respiratory distress syndrome (ARDS), for which there is no greater origin. Imbalances of the biological processes controlling immunity and tissue integrity increase the likelihood that lung infections progress to pneumonia, demanding a better understanding of when, where, and how host signals integrate to confer protection. Here we propose the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) as a regulatory node for shaping inflammation in the pneumonic lung. While this receptor has well- established roles in promoting vascular injury in patients with atherosclerosis, its function in the lungs is unknown. Our preliminary results from both mice and humans indicate substantial accumulation of LOX-1 in pneumonic lungs. Moreover, our mouse studies reveal that LOX-1 in the airspace compartment, particularly that originating from hematopoietic cells, dampens immunopathology in the infected lung. This contrasts the harmful roles of LOX-1 during cardiovascular disease, implicating the alveolar milieu as a unique niche for LOX-1-dependent tissue fortification. Although LOX-1 has never been investigated in the context of lung infections, we posit that its expression by alveolar macrophages and neutrophils serves as a countermeasure to dampen pneumonia-induced inflammation and maintain tissue integrity. Therefore, we will test the central hypothesis that LOX-1 on airspace myeloid cells bolsters tissue protection in response to lung infection. This will be addressed by pursuing the following 3 aims: Aim 1) Test the hypothesis hematopoietic cellular subsets prominently contribute to LOX-1-driven tissue protection in the infected lung; Aim 2) Test the hypothesis that LOX-1 promotes efferocytosis and repolarization in alveolar macrophages to limit immunopathology during pneumonia; and Aim 3) Test the hypothesis that LOX-1 guides alveolar neutrophils towards an MDSC-like state through altered lipid handling and anti-inflammatory feedback, countering infection-induced injury. Our proposed studies will leverage complementary in vivo and ex vivo approaches in order to reveal basic biological mechanisms of tissue homeostasis during pneumonia, paving the way for novel clinical interventions in patients with or at risk for this disease.