P2X受体拮抗作用可改善脓毒症大鼠模型的肾功能障碍。
P2X receptor antagonism ameliorates renal dysfunction in a rat model of sepsis.
作者信息
Arulkumaran Nishkantha, Sixma Marije L, Pollen Sean, Ceravola Elias, Jentho Elisa, Prendecki Maria, Bass Paul S, Tam Frederick W K, Unwin Robert J, Singer Mervyn
机构信息
Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom.
Division of Medicine, Department of Nephrology, University College London, London, United Kingdom.
出版信息
Physiol Rep. 2018 Mar;6(5). doi: 10.14814/phy2.13622.
Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP-sensitive P2X receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid-resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this purinergic receptor to renal dysfunction in sepsis. Six and 24 h time-points were chosen to represent early and established sepsis, respectively. A selective P2X receptor antagonist (A-438079) dissolved in dimethyl sulfoxide (DMSO) was infused 2 h following induction of sepsis. Compared with sham-operated animals, septic animals had significant increases in heart rate (-1(-4 to 8)% vs. 21(12-26)%; P = 0.003), fever (37.4(37.2-37.6)°C vs. 38.6(38.2-39.0)°C; P = 0.0009), and falls in serum albumin (29(27-30)g/L vs. 26(24-28); P = 0.0242). Serum IL-1β (0(0-10)(pg/mL) vs. 1671(1445-33778)(pg/mL); P < 0.001) and renal IL-1β (86(50-102)pg/mg protein vs. 200 (147-248)pg/mg protein; P = 0.0031) were significantly elevated in septic compared with sham-operated animals at 6 h. Serum creatinine was elevated in septic animals compared with sham-operated animals at 24 h (23(22-25) μmol/L vs. 28 (25-30)μmol/L; P = 0.0321). Renal IL-1β levels were significantly lower in A-438079-treated animals compared with untreated animals at 6 h (70(55-128)pg/mg protein vs. 200(147-248)pg/mg protein; P = 0.021). At 24 h, compared with untreated animals, A-438079-treated animals had more rapid resolution of tachycardia (22(13-36)% vs. -1(-6 to 7)%; P = 0.019) and fever (39.0(38.6-39.1)°C vs. 38.2(37.6-38.7)°C; P < 0.024), higher serum albumin (23(21-25)g/L vs. (27(25-28)g/L); P = 0.006), lower arterial lactate (3.2(2.5-4.3)mmol/L vs. 1.4(0.9-1.8)mmol/L; P = 0.037), and lower serum creatinine concentrations (28(25-30)μmol/L vs. 22(17-27)μmol/L; P = 0.019). P2X A treatment ameliorates the systemic inflammatory response and renal dysfunction in this clinically relevant model of sepsis-related AKI.
脓毒症是一个与严重器官功能障碍和高死亡率相关的主要临床问题。ATP 敏感性 P2X 受体激活 NLRP3 炎性小体，是先天性免疫系统的关键组成部分。我们使用粪便性腹膜炎和急性肾损伤（AKI）的液体复苏大鼠模型，来研究这种嘌呤能受体在脓毒症所致肾功能障碍中的作用。分别选择 6 小时和 24 小时这两个时间点来代表早期脓毒症和已确诊的脓毒症。在诱导脓毒症 2 小时后，注入溶解于二甲基亚砜（DMSO）的选择性 P2X 受体拮抗剂（A - 438079）。与假手术动物相比，脓毒症动物的心率显著增加（-1（-4 至 8）% 对 21（12 - 26）%；P = 0.003）、发热（37.4（37.2 - 37.6）°C 对 38.6（38.2 - 39.0）°C；P = 0.0009），血清白蛋白水平下降（29（27 - 30）g/L 对 26（24 - 28）；P = 0.0242）。与假手术动物相比，脓毒症动物在 6 小时时血清白细胞介素 - 1β（IL - 1β）（0（0 - 10）（pg/mL）对 1671（1445 - 33778）（pg/mL）；P < 0.001）和肾脏 IL - 1β（86（50 - 102）pg/mg 蛋白对 200（147 - 248）pg/mg 蛋白；P = 0.0031）显著升高。与假手术动物相比，脓毒症动物在 24 小时时血清肌酐升高（23（22 - 25）μmol/L 对 28（25 - 30）μmol/L；P = 0.0321）。与未治疗动物相比，A - 438079 治疗的动物在 6 小时时肾脏 IL - 1β 水平显著降低（70（55 - 128）pg/mg 蛋白对 200（147 - 248）pg/mg 蛋白；P = 0.021）。在 24 小时时，与未治疗动物相比，A - 438079 治疗的动物心动过速（22（13 - 36）% 对 -1（-6 至 7）%；P = 0.019）和发热（39.0（38.6 - 39.1）°C 对 38.2（37.6 - 38.7）°C；P < 0.024）缓解更快，血清白蛋白更高（23（21 - 25）g/L 对（27（25 - 28）g/L）；P = 0.006），动脉血乳酸更低（3.2（2.5 - 4.3）mmol/L 对 1.4（0.9 - 1.8）mmol/L；P = 0.037），血清肌酐浓度更低（28（25 - 30）μmol/L 对 22（17 - 27）μmol/L；P = 0.019）。在这个与脓毒症相关的 AKI 的临床相关模型中，P2X A 治疗改善了全身炎症反应和肾功能障碍。
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