P2X7 receptor activation contributes to an initial upstream mechanism of lipopolysaccharide-induced vascular dysfunction.
P2X7 receptor activation contributes to an initial upstream mechanism of lipopolysaccharide-induced vascular dysfunction.
复制标题
DOI：
10.1042/cs20120479
复制
发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Webb RC
中科院分区：
文献类型：
--
作者：
Chiao CW;da Silva-Santos JE;Giachini FR;Tostes RC;Su MJ;Webb RC
促炎细胞因子、趋化因子和活性氧在内毒素血症中过量产生。然而，试图同时抑制所有这些炎症信号通路以预防内毒素血症是困难的。在先前的研究中，我们观察到P2 X7受体的激活引起白细胞介素（IL）-1β从脂多糖（LPS）孵育的血管中释放。在本研究中，我们假设P2 X7受体激活是LPS治疗后导致血管功能障碍的初始事件。在P2 X7敲除（P2 X7 KO）小鼠中，LPS诱导的平均动脉血压降低和对去甲肾上腺素的升压反应减弱。在C57 BL/6（野生型，WT）小鼠和P2 X7 KO小鼠中，也观察到LPS处理的离体肠系膜动脉中对苯丙氨酸的低反应性，该低反应性被IL-1受体拮抗剂（IL 1 ra）、L-NAME和吲哚美辛阻止。此外，IL 1 ra + L-NAME治疗对LPS诱导的血管低反应性产生了叠加抑制，表明IL-1β和一氧化氮合酶（NOS）之间存在不同的信号通路。在WT小鼠和P2 X7 KO小鼠中，通过ELISA和蛋白质印迹法测定的LPS诱导的IL-1β、肿瘤坏死因子（TNF）-α、IL-10、血管eNOS和环氧合酶（考克斯）2蛋白表达的血浆水平被IL 1 ra抑制。这些结果表明，P2 X7受体激活涉及LPS诱导的血管功能障碍的初始上游机制，其与IL-1β介导的eNOS、COX 2激活和TNF-α释放相关。
Pro-inflammatory cytokines, chemokines and the reactive oxygen species are excessively produced in endotoxemia. However, attempting to inhibit all of these inflammatory signaling pathways at the same time in order to prevent endotoxemia is difficult. In a previous study we observed that activation of P2X7 receptors elicited the release of interleukin (IL)-1β from lipopolysaccharide (LPS)-incubated vessels. In the present study we hypothesize that P2X7 receptor activation is the initial event leading to vascular dysfunction following LPS treatment. LPS-induced decreases in mean arterial blood pressure and pressor responses to norepinephrine were attenuated in P2X7 knockout (P2X7KO) mice. Hypo-reactivity to phenylephrine in isolated mesenteric arteries by LPS treatment was also observed in C57BL/6 (wild type, WT) mice, which was prevented by IL-1 receptor antagonist (IL1ra), L-NAME and indomethacin, and in P2X7KO mice. Additionally, treatment with IL1ra plus L-NAME produced an additive inhibition of LPS-induced vascular hypo-reactivity, suggesting different signaling pathways between IL-1β and nitric oxide synthase (NOS). LPS-induced plasma levels of IL-1β, tumor necrosis factor (TNF)-α, IL-10, vascular eNOS and cyclooxygenase (COX)2 protein expression, as determined by ELISA and western blot, observed in WT mice were inhibited by IL1ra and in P2X7KO mice. These results suggest that P2X7 receptor activation involves an initial upstream mechanism of LPS-induced vascular dysfunction, which is associated with IL-1β-mediated eNOS, COX2 activation and TNF-α release.