Center for Translational Research in Biomedical Sciences, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, 83301, Taiwan.
J Neuroinflammation. 2012 Sep 7;9:212. doi: 10.1186/1742-2094-9-212.
In addition to systemic inflammation, neuroinflammation in the brain, which enhances sympathetic drive, plays a significant role in cardiovascular diseases, including hypertension. Oxidative stress in rostral ventrolateral medulla (RVLM) that augments sympathetic outflow to blood vessels is involved in neural mechanism of hypertension. We investigated whether neuroinflammation and oxidative stress in RVLM contribute to hypertension following chronic systemic inflammation.
In normotensive Sprague-Dawley rats, systemic inflammation was induced by infusion of Escherichia coli lipopolysaccharide (LPS) into the peritoneal cavity via an osmotic minipump. Systemic arterial pressure and heart rate were measured under conscious conditions by the non-invasive tail-cuff method. The level of the inflammatory markers in plasma or RVLM was analyzed by ELISA. Protein expression was evaluated by Western blot or immunohistochemistry. Tissue level of superoxide anion (O(2)(-)) in RVLM was determined using the oxidation-sensitive fluorescent probe dihydroethidium. Pharmacological agents were delivered either via infusion into the cisterna magna with an osmotic minipump or microinjection bilaterally into RVLM.
Intraperitoneal infusion of LPS (1.2 mg/kg/day) for 14 days promoted sustained hypertension and induced a significant increase in plasma level of C-reactive protein, tumor necrosis factor-α (TNF-α), or interleukin-1β (IL-1β). This LPS-induced systemic inflammation was accompanied by activation of microglia, augmentation of IL-1β, IL-6, or TNF-α protein expression, and O(2)(-) production in RVLM, all of which were blunted by intracisternal infusion of a cycloxygenase-2 (COX-2) inhibitor, NS398; an inhibitor of microglial activation, minocycline; or a cytokine synthesis inhibitor, pentoxifylline. Neuroinflammation in RVLM was also associated with a COX-2-dependent downregulation of endothelial nitric oxide synthase and an upregulation of intercellular adhesion molecule-1. Finally, the LPS-promoted long-term pressor response and the reduction in expression of voltage-gated potassium channel, Kv4.3 in RVLM were antagonized by minocycline, NS398, pentoxifylline, or a superoxide dismutase mimetic, tempol, either infused into cisterna magna or microinjected bilaterally into RVLM. The same treatments, on the other hand, were ineffective against LPS-induced systemic inflammation.
These results suggest that systemic inflammation activates microglia in RVLM to induce COX-2-dependent neuroinflammation that leads to an increase in O(2)(-) production. The resultant oxidative stress in RVLM in turn mediates neurogenic hypertension.
除了全身炎症外，大脑中的神经炎症增强了交感神经驱动，在包括高血压在内的心血管疾病中发挥了重要作用。增加血管交感神经输出的延髓头端腹外侧区（RVLM）氧化应激参与了高血压的神经机制。我们研究了慢性全身炎症后 RVLM 中的神经炎症和氧化应激是否导致高血压。
在正常血压的 Sprague-Dawley 大鼠中，通过腹腔内渗透微型泵将大肠杆菌脂多糖（LPS）输注到腹腔中诱导全身炎症。通过非侵入性尾套法在清醒状态下测量系统动脉压和心率。通过 ELISA 分析血浆或 RVLM 中炎症标志物的水平。通过 Western blot 或免疫组织化学评估蛋白质表达。使用氧化敏感荧光探针二氢乙啶测定 RVLM 中超氧阴离子（O(2)(-))的组织水平。药物通过颅内渗透微型泵或双侧 RVLM 微注射给予。
14 天腹腔内输注 LPS（1.2mg/kg/天）可促进持续性高血压，并显著增加血浆 C 反应蛋白、肿瘤坏死因子-α（TNF-α）或白细胞介素-1β（IL-1β）水平。这种 LPS 诱导的全身炎症伴随着小胶质细胞的激活、IL-1β、IL-6 或 TNF-α 蛋白表达的增加以及 RVLM 中 O(2)(-)的产生，所有这些都被 COX-2 抑制剂 NS398、小胶质细胞激活抑制剂米诺环素或细胞因子合成抑制剂己酮可可碱颅内渗透所减弱。RVLM 中的神经炎症也与 COX-2 依赖性内皮型一氧化氮合酶下调和细胞间黏附分子-1 上调有关。最后，米诺环素、NS398、己酮可可碱或超氧化物歧化酶类似物 Tempo 通过颅内渗透或双侧 RVLM 微注射，拮抗了 LPS 促进的长期升压反应和 RVLM 中电压门控钾通道 Kv4.3 的表达减少。另一方面，这些相同的治疗方法对 LPS 诱导的全身炎症无效。
这些结果表明，全身炎症激活 RVLM 中的小胶质细胞，引发 COX-2 依赖性神经炎症，导致 O(2)(-)产生增加。RVLM 中的这种氧化应激反过来介导了神经性高血压。
