FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia reperfusion injury
FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia reperfusion injury
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DOI：
10.1016/j.jvs.2008.09.056
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发表时间：
2009-03-01
影响因子：
4.3
通讯作者：
Hauet, Thierry
中科院分区：
文献类型：
--
作者：
Cau, Jerome;Favreau, Frederic;Hauet, Thierry
目的：继发于诱导性热缺血（WI）的急性肾小管坏死（ATN）导致炎症和延迟性纤维化过程，并且仍然是一个常见的临床问题，具有严重的后果。由于肿瘤坏死因子-a (TNF-α) 是一种重要的促炎因子，与急性肾缺血再灌注损伤 (IRI) 的病理生理学有关，因此我们假设 FR167653 (FR) 是 TNF-α 和白细胞介素 1 β 产生的有效抑制剂，可能会降低 IRI。 方法。雄性猪通过双侧夹紧肾蒂 90 分钟（WI90），或对侧肾切除（1/2N x 90）后单侧肾夹紧（90 分钟），或不切除对侧肾的单侧肾夹紧（WIuni90）诱导 IRI。治疗组（FRW190、FR1/2N x 90 或 FRWIuni90）在 WI 前 60 分钟、WI 期间和再灌注期间静脉注射 FR（1 mg/kg/h），并连续 3 小时（1 mg/kg/h）。再灌注后第1天至3个月期间收集血液和尿液样本以评估肾功能。 3个月时切除肾脏并收集肾组织用于形态学和炎症评估以及蛋白质分析。实验组与假手术组（对照组）和无肾缺血的半肾切除组（Unif）进行比较。结果。由于没有尿液产生或状况不佳，三只 WI90 动物 (43%) 和五只 1/2N x 90 (70%) 在第 7 天被安乐死并进行尸检。 FR治疗后死亡率显着改善。对照组、Unif、WIuni90 和 FR 组的存活率为 100%。在 Unif 组中，PR 显着减少肾衰竭和双侧肾缺血（P < .05）。 3 个月时，FR 治疗组的蛋白尿显着减少 (P < .01)。经 FR 处理的猪中炎症细胞计数也显着减少（CD3 阳性细胞 P < .01）。短暂性脑缺血的第二个方面是 3 个月时确定的纤维化过程。 FR 治疗的特点是肾纤维化减少，特别是在 Unif 组中。 FR治疗组中TNF-α蛋白表达减少。结论：这是第一个证据表明FR降低了严重缺血模型中WI的早期和长期影响。这种作用对于纤维化和炎症尤其显着，纤维化和炎症会导致患者肾功能恶化。 （瓦斯克外科杂志 2009 年；49：728-40。）
Objective: Acute tubular necrosis (ATN) secondary to induced warm ischemia (WI) results in inflammatory and delayed fibrotic processes and remains a common clinical problem with serious consequences. Because tumor necrosis factor-a (TNF-alpha) is a prominent proinflammatory factor implicated in the pathophysiology of acute renal ischemia reperfusion injury (IRI), we hypothesized that FR167653 (FR), a potent inhibitor of TNF-alpha and interleukin-1 beta production, may reduce IRI.Methods. IRI was induced in male pigs by bilateral clamping of the renal pedicle for 90 minutes (WI90), or unilateral renal clamping (90 minutes) after contralateral nephrectomy (1/2N x 90), or unilateral renal clamping without contralateral nephrectomy (WIuni90). FR was administered intravenously 60 minutes before WI (1 mg/kg/h), during WI, and continuously for 3 hours (1 mg/kg/h) during reperfusion in treated groups (FRW190, FR1/2N x 90, or FRWIuni90). Blood and urine samples were collected between day 1 and 3 months after reperfusion for assessment of renal function. Kidneys were excised and renal tissues were collected at 3 months for morphologic and inflammation evaluation and protein analysis. Experimental groups were compared with sham operated (control) and heminephrectomized (Unif) groups without renal ischemia.Results. Three WI90 animals (43%) and five 1/2N x 90 (70%) were euthanized and necropsied at day 7 because of no urine production or poor conditions. Mortality was significantly improved after FR treatment. Survival was 100% in the control, Unif, WIuni90, and FR groups. In Unif groups, PR significantly reduced renal failure and bilateral renal ischemia (P < .05). At 3 months, proteinuria was significantly reduced in FR-treated groups (P < .01). Inflammatory cells count was also dramatically diminished in FR-treated pigs (P < .01 for CD3-positive cells). The second aspect of transient ischemia is the fibrotic process determined at 3 months. FR treatment was characterized by a reduction of renal fibrosis, particularly in Unif groups. TNF-alpha protein expression was diminished in FR-treated groups.Conclusion: This is the first evidence that FR reduced the early and long-term effect of WI in the severe ischemia model. This effect was particularly marked against fibrosis and inflammation, which would contribute to deterioration of a patient's renal function. (J Vasc Surg 2009;49:728-40.)