Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester NY 14642 United States.
Microbiology & Immunology, University of Rochester School of Medicine and Dentistry, Rochester NY 14642 United States.
J Stroke Cerebrovasc Dis. 2020 Sep;29(9):104942. doi: 10.1016/j.jstrokecerebrovasdis.2020.104942. Epub 2020 May 14.
Studies implicate the lung in moderating systemic immune activation via effects on circulating leukocytes. In this study, we investigated whether targeted expression of the antioxidant extracellular superoxide dismutase (SOD3) within the lung would influence post-ischemic peripheral neutrophil activation and CNS reperfusion injury.
Adult, male mice expressing human SOD3 within type II pneumocytes were subjected to 15 min of transient global cerebral ischemia. Three days post-reperfusion, lung and brain tissue was collected and analyzed by immunohistochemistry for inflammation and injury markers. In vitro motility and neurotoxicity assays were conducted to ascertain the direct effects of hSOD3 on PMN activation. Results were compared against C57BL/6 age and sex-matched controls.
Relative to wild-type controls, hSOD3 heterozygous mice exhibited a reduction in lung inflammation, blood-brain barrier damage, and post-ischemic neuronal injury within the hippocampus and cortex. PMNs harvested from hSOD3 mice were also resistant to LPS priming, slower-moving, and less toxic to primary neuronal cultures.
Constitutive, focal expression of hSOD3 is neuroprotective in a model of global cerebral ischemia-reperfusion injury. The underlying mechanism of SOD3-dependent protection is attributable in part to effects on the activation state and toxic potential of circulating neutrophils. These results implicate lung-brain coupling as a determinant of cerebral ischemia-reperfusion injury and highlight post-stroke lung inflammation as a potential therapeutic target in acute ischemic cerebrovascular injuries.
研究表明，肺部通过对循环白细胞的影响来调节全身免疫激活。在这项研究中，我们研究了肺内靶向表达抗氧化剂细胞外超氧化物歧化酶（SOD3）是否会影响缺血后外周中性粒细胞的激活和中枢神经系统再灌注损伤。
在Ⅱ型肺泡细胞中表达人 SOD3 的成年雄性小鼠接受 15 分钟短暂全脑缺血。再灌注后 3 天，收集肺和脑组织，通过免疫组织化学分析炎症和损伤标志物。进行体外运动和神经毒性测定，以确定 hSOD3 对 PMN 激活的直接影响。结果与 C57BL/6 年龄和性别匹配的对照进行比较。
与野生型对照组相比，hSOD3 杂合子小鼠的肺部炎症、血脑屏障损伤以及海马和皮质内缺血后神经元损伤减少。从 hSOD3 小鼠中分离的 PMN 也对 LPS 引发的反应具有抗性，运动速度较慢，对原代神经元培养物的毒性较小。
在全脑缺血再灌注损伤模型中，hSOD3 的组成型、局灶性表达具有神经保护作用。SOD3 依赖性保护的潜在机制部分归因于对循环中性粒细胞激活状态和毒性潜力的影响。这些结果表明肺-脑耦联是脑缺血再灌注损伤的决定因素，并强调了脑卒中后肺炎症作为急性缺血性脑血管损伤的潜在治疗靶点。
