Tassiopoulos A K, Carlin R E, Gao Y, Pedoto A, Finck C M, Landas S K, Tice D G, Marx W, Hakim T S, McGraw D J
Department of Surgery, State University of New York Health Science Center, Syracuse 13210, USA.
J Vasc Surg. 1997 Oct;26(4):647-56. doi: 10.1016/s0741-5214(97)70065-x.
Acute aortic occlusion with subsequent ischemia/reperfusion (I/R) of the lower extremities is known to predispose to lung injury. The pathophysiologic mechanisms of this injury are not clear. In the present study, we studied the role of tumor necrosis factor (TNF) and nitric oxide (NO) in lung injury caused by lower extremity I/R.
A rat model in which the infrarenal aorta was cross-clamped for 3 hours followed by 1 hour of reperfusion was used. The rats were randomized into five groups: group 1, aorta exposed but not clamped; group 2, aorta clamped for 3 hours, followed by 1 hour of reperfusion; group 3, 1 mg/kg dexamethasone administered before the aorta was clamped; group 4, 25 mg aminoguanidine, a specific inducible NO synthase (iNOS) inhibitor, administered before the aorta was clamped; and group 5, 2 mg/kg TNFbp, a PEG-ylated dimeric form of the high-affinity p55 TNF receptor I (RI), administered before the aorta was clamped. NO concentration in the exhaled gas (ENO) was measured, as an index of NO production by the lung, in 30 minute intervals during I/R. Serial arterial blood samples for TNF assay were obtained during the course of the experiment. At the end of the experiment, the lungs were removed and histologically examined for evidence of injury.
ENO in group 2 increased from 0.7 +/- 0.3 ppb at baseline to 54.3 +/- 7.5 ppb at the end of ischemia and remained stable during reperfusion (54.6 +/- 8.5 ppb at the end of reperfusion). ENO production was blocked by aminoguanidine, by dexamethasone, and by TNFbp given before aortic occlusion. Serum TNF in groups 2, 3 and 4 increased rapidly during early ischemia, reaching its peak value 60 minutes after occlusion of the aorta, then gradually declined to baseline levels at the end of ischemia, and remained low during reperfusion. TNFbp decreased serum TNF concentration significantly when it was given before aortic occlusion. Histologic examination of the lungs at the end of the experiment revealed that aminoguanidine, dexamethasone, and TNFbp had a protective effect on the lungs.
Serum TNF increases rapidly during lower extremity ischemia and causes increased production of NO from the lung by upregulating iNOS. Increased NO is associated with more severe lung injury, and iNOS blockade has beneficial effects on the lung. TNF blockade before ischemia decreases NO production by the lung and attenuates lung injury. ENO can be used as an early marker of lung injury caused by lower extremity I/R.
已知急性主动脉闭塞并随后出现下肢缺血/再灌注（I/R）易导致肺损伤。这种损伤的病理生理机制尚不清楚。在本研究中，我们研究了肿瘤坏死因子（TNF）和一氧化氮（NO）在下肢I/R所致肺损伤中的作用。
采用一种大鼠模型，即肾下腹主动脉交叉夹闭3小时，随后再灌注1小时。将大鼠随机分为五组：第1组，暴露主动脉但不夹闭；第2组，主动脉夹闭3小时，随后再灌注1小时；第3组，在夹闭主动脉前给予1mg/kg地塞米松；第4组，在夹闭主动脉前给予25mg氨基胍，一种特异性诱导型一氧化氮合酶（iNOS）抑制剂；第5组，在夹闭主动脉前给予2mg/kg TNFbp，一种聚乙二醇化的高亲和力p55肿瘤坏死因子受体I（RI）的二聚体形式。在I/R期间，每隔30分钟测量呼出气体中的NO浓度（ENO），作为肺产生NO的指标。在实验过程中获取系列动脉血样本用于TNF检测。实验结束时，取出肺组织并进行组织学检查以寻找损伤证据。
第2组的ENO从基线时的0.7±0.3ppb在缺血结束时增加至54.3±7.5ppb，并在再灌注期间保持稳定（再灌注结束时为54.6±8.5ppb）。氨基胍、地塞米松以及在主动脉闭塞前给予的TNFbp均可阻断ENO的产生。第2、3和4组的血清TNF在早期缺血期间迅速升高，在主动脉闭塞60分钟后达到峰值，然后在缺血结束时逐渐降至基线水平，并在再灌注期间保持较低水平。在主动脉闭塞前给予TNFbp可显著降低血清TNF浓度。实验结束时对肺组织进行组织学检查发现，氨基胍、地塞米松和TNFbp对肺具有保护作用。
在下肢缺血期间血清TNF迅速升高，并通过上调iNOS导致肺产生更多的NO。NO增加与更严重的肺损伤相关，而阻断iNOS对肺具有有益作用。缺血前阻断TNF可减少肺产生NO并减轻肺损伤。ENO可作为下肢I/R所致肺损伤的早期标志物。
