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

摘要 肺炎是世界范围内发病率和死亡率的主要原因，这在很大程度上是由于急性肺炎的发作。 呼吸窘迫综合征（ARDS），没有更大的起源。生物不平衡 控制免疫力和组织完整性的过程增加了肺部感染进展到 肺炎，需要更好地了解何时，何地以及如何整合宿主信号， 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 L0 X-1作为用于形成肺炎肺中的炎症的调节节点。尽管这种受体- 在促进动脉粥样硬化患者血管损伤中的作用，其在肺中的功能是 未知我们对小鼠和人类的初步结果表明，LOX-1在小鼠和人类中大量积累， 肺炎性肺。此外，我们的小鼠研究表明，LOX-1在空气舱，特别是 它来源于造血细胞，抑制了受感染肺部的免疫病理学。这与 LOX-1在心血管疾病中的有害作用，暗示肺泡环境是LOX-1的独特生态位。 LOX-1依赖性组织强化。尽管LOX-1从未在肺组织中被研究过， 感染时，我们认为肺泡巨噬细胞和中性粒细胞的表达是一种对策， 以抑制肺炎引起的炎症并保持组织完整性。因此，我们将测试中央 假设空气中髓样细胞上的LOX-1支持响应于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）测试假设造血细胞亚群 显著地有助于LOX-1驱动的感染肺中的组织保护;目的2）检验以下假设， LOX-1促进肺泡巨噬细胞的红细胞增多和复极化以限制免疫病理学， 目的3）检验LOX-1引导肺泡中性粒细胞向MDSC样细胞分化的假设。 通过改变脂质处理和抗炎反馈，对抗感染引起的损伤。我们 拟议的研究将利用互补的体内和体外方法，以揭示基本的 肺炎期间组织稳态的生物学机制，为新型临床干预措施铺平了道路 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.