Department of Clinical and Experimental Medicine, University of Eastern Piedmont Amedeo Avogadro, Corso Mazzini 18, Novara, Italy.
Crit Care. 2010;14(2):R45. doi: 10.1186/cc8932. Epub 2010 Mar 26.
Mechanical ventilation (MV) can injure the lungs and contribute to an overwhelming inflammatory response, leading to acute renal failure (ARF). We previously showed that poly(adenosine diphosphate-ribose) polymerase (PARP) is involved in the development of ventilator-induced lung injury (VILI) and the related ARF, but the mechanisms underneath remain unclear. In the current study we therefore tested the hypothesis that renal blood flow and endothelial, functional and tissue changes in the kidney of rats with lipopolysaccharide (LPS)-induced lung injury aggravated by MV, is caused, in part, by activation of PARP by peroxynitrite.
Anesthetized Sprague Dawley rats (n = 31), were subjected to intratracheal instillation of lipopolysaccharide at 10 mg/kg followed by 210 min of mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (19 mL/kg) with zero positive end-expiratory pressure in the presence or absence of a peroxynitrite decomposition catalyst, WW85 or a PARP inhibitor, PJ-34. During the experiment, hemodynamics and blood gas variables were monitored. At time (t) t = 0 and t = 180 min, renal blood flow was measured. Blood and urine were collected for creatinine clearance measurement. Arcuate renal arteries were isolated for vasoreactivity experiment and kidneys snap frozen for staining.
High tidal volume ventilation resulted in lung injury, hypotension, renal hypoperfusion and impaired renal endothelium-dependent vasodilation, associated with renal dysfunction and tissue changes (leukocyte accumulation and increased expression of neutrophil gelatinase-associated lipocalin). Both WW85 and PJ-34 treatments attenuated lung injury, preserved blood pressure, attenuated renal endothelial dysfunction and maintained renal blood flow. In multivariable analysis, renal blood flow improvement was, independently from each other, associated with both maintained blood pressure and endothelium-dependent vasodilation by drug treatment. Finally, drug treatment improved renal function and reduced tissue changes.
The peroxynitrite-induced PARP activation is involved in renal hypoperfusion, impaired endothelium-dependent vasodilation and resultant dysfunction, and injury, in a model of lung injury.
机械通气（MV）可损伤肺部并导致过度炎症反应，从而导致急性肾衰竭（ARF）。我们之前的研究表明，聚（腺嘌呤二核苷酸-核糖）聚合酶（PARP）参与了呼吸机诱导的肺损伤（VILI）和相关的 ARF 的发展，但其中的机制尚不清楚。因此，在本研究中，我们假设脂多糖（LPS）诱导的肺损伤大鼠在接受 MV 治疗后，其肾脏的肾血流量和内皮、功能和组织变化部分是由过氧亚硝酸盐激活 PARP 引起的。
麻醉后的 Sprague Dawley 大鼠（n = 31），经气管内滴注 LPS 10 mg/kg，然后进行机械通气 210 min，低潮气量（6 mL/kg），呼气末正压 5 cm H2O 或大潮气量（19 mL/kg），零呼气末正压，同时给予过氧亚硝酸盐分解催化剂 WW85 或 PARP 抑制剂 PJ-34。在实验过程中，监测血流动力学和血气变量。在时间（t）t = 0 和 t = 180 min 时，测量肾血流量。采集血液和尿液以测量肌酐清除率。分离弓状肾动脉进行血管反应性实验，肾脏组织立即冷冻用于染色。
大潮气量通气导致肺损伤、低血压、肾灌注不足和肾内皮依赖性血管舒张受损，同时伴有肾功能障碍和组织变化（白细胞聚集和中性粒细胞明胶酶相关脂质运载蛋白表达增加）。WW85 和 PJ-34 治疗均减轻了肺损伤，维持了血压，减轻了肾内皮功能障碍，并维持了肾血流量。多变量分析表明，肾血流量的改善与药物治疗分别独立地与血压的维持和内皮依赖性血管舒张有关。最后，药物治疗改善了肾功能并减少了组织变化。
过氧亚硝酸盐诱导的 PARP 激活参与了肺损伤模型中的肾灌注不足、内皮依赖性血管舒张受损以及由此导致的功能和损伤。
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