Pharmacology Department, College of Medicine, Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, United States.
Front Immunol. 2019 Dec 10;10:2885. doi: 10.3389/fimmu.2019.02885. eCollection 2019.
Patients with Type 2 Diabetes Mellitus (T2DM) suffer from a higher incidence and severity of pulmonary infections. This is likely due to immune impairment and structural abnormalities caused by T2DM-induced oxidative stress (OS) and chronic inflammation. Modulation of the Renin Angiotensin System (RAS) through blockade of the actions of angiotensin II (AII), or inducing the protective pathway, has the potential to reduce these pathological pathways. The effects of Angiotensin 1-7 [A(1-7)] and NorLeu-A(1-7) [NorLeu], ligands of the protective RAS, on the innate immune response were evaluated in the mouse model of T2DM. Only NorLeu treatment reduced the structural pathologies in the lung caused by T2DM. A decreased in bactericidal activity and phagocytosis in diabetic animals was also observed; both A(1-7) and NorLeu treatment restored these functions. Myeloid progenitor CFUs were reduced and neutrophil/progenitor OS was increased in saline-treated mice, and was reversed by A(1-7) and NorLeu treatment. These results demonstrate the adverse effects of diabetes on factors that contribute to pulmonary infections and the therapeutic potential of protective RAS peptides. Overall, RAS-modification may be a viable therapeutic target to treat diabetic complications that are not addressed by glucose lowering drugs.
2 型糖尿病（T2DM）患者的肺部感染发生率和严重程度更高。这可能是由于 T2DM 引起的氧化应激（OS）和慢性炎症导致的免疫损伤和结构异常。通过阻断血管紧张素 II（AII）的作用或诱导保护途径来调节肾素血管紧张素系统（RAS），有可能减轻这些病理途径。评估了血管紧张素 1-7 [A(1-7)]和 NorLeu-A(1-7) [NorLeu]，即保护 RAS 的配体，对 T2DM 小鼠模型中固有免疫反应的影响。只有 NorLeu 治疗可减轻 T2DM 引起的肺部结构病理学变化。还观察到糖尿病动物的杀菌活性和吞噬作用降低；A(1-7)和 NorLeu 治疗均可恢复这些功能。在接受盐水治疗的小鼠中，髓样祖细胞 CFU 减少，中性粒细胞/祖细胞 OS 增加，而 A(1-7)和 NorLeu 治疗可逆转这种情况。这些结果表明糖尿病对导致肺部感染的因素有不良影响，而保护 RAS 肽具有治疗潜力。总体而言，RAS 修饰可能是一种可行的治疗靶点，可治疗葡萄糖降低药物无法解决的糖尿病并发症。
