Linas S L, Whittenburg D, Parsons P E, Repine J E
Denver General Hospital, Colorado, USA.
Kidney Int. 1995 Nov;48(5):1584-91. doi: 10.1038/ki.1995.451.
The role of neutrophils in acute renal failure (ARF) is controversial. Although ARF occurs in neutropenic subjects, we found that ischemic kidneys activated neutrophils to cause ARF in isolated perfused rat kidneys. To further define the interaction between neutrophils and renal ischemia, we performed quantitative assessment of neutrophil accumulation during renal ischemia. Non-ischemic and ischemic rat kidneys were perfused by the isolated kidney technique with unstimulated, primed, or fully activated, indium-labeled neutrophils. Neutrophil accumulation was quantitated by measuring indium retention after 60 minutes of perfusion. In non-ischemic kidneys, only activated neutrophils were retained while after 20 minutes of renal ischemia, unstimulated as well as primed neutrophils were retained. Following 10 minutes of ischemia, primed neutrophils (but not unstimulated neutrophils) were retained. In the presence of neutrophil retention, there were decreases in GFR and tubular sodium reabsorption. To determine the role of ICAM 1 in ischemic injury, rats were treated with anti-ICAM 1 prior to ischemia and ischemic kidneys were reperfused with unstimulated neutrophils and anti-ICAM 1. After ischemia, the neutrophil component of reperfusion injury in isolated kidneys was prevented with anti-ICAM 1. Oxygen metabolites have been shown to induce EC expression of ICAM 1. To determine the role of ICAM 1 in oxidant-mediated renal injury, ischemic isolated kidneys were reperfused with catalase (CAT) and non-ischemic kidneys were perfused with hydrogen peroxide. Following ischemia, reperfusion with CAT prevented neutrophil retention and injury. In non-ischemic kidneys, hydrogen peroxide caused primed neutrophil retention, activation and renal injury which were completely prevented with anti-ICAM 1.
(1) Ischemic kidneys cause neutrophil retention, activation, and worsening of renal injury in isolated kidneys; and 2) neutrophil retention is dependent on the state of neutrophil activation, duration of renal ischemia and is mediated by oxygen metabolites and ICAM 1. This synergism could account for the high frequency of ARF in conditions such as sepsis where there is both renal hypoperfusion and neutrophil priming.
中性粒细胞在急性肾衰竭（ARF）中的作用存在争议。尽管ARF发生在中性粒细胞减少的患者中，但我们发现缺血的肾脏会激活中性粒细胞，从而在离体灌注的大鼠肾脏中导致ARF。为了进一步明确中性粒细胞与肾脏缺血之间的相互作用，我们对肾脏缺血期间中性粒细胞的积聚进行了定量评估。采用离体肾脏技术，用未刺激的、预激活的或完全激活的铟标记中性粒细胞灌注非缺血和缺血大鼠的肾脏。灌注60分钟后，通过测量铟的潴留量来定量中性粒细胞的积聚。在非缺血肾脏中，仅保留激活的中性粒细胞，而在肾脏缺血20分钟后，未刺激的以及预激活的中性粒细胞均被保留。缺血10分钟后，预激活的中性粒细胞（而非未刺激的中性粒细胞）被保留。在存在中性粒细胞潴留的情况下，肾小球滤过率（GFR）和肾小管钠重吸收降低。为了确定细胞间黏附分子1（ICAM 1）在缺血性损伤中的作用，在缺血前用抗ICAM 1治疗大鼠，并用未刺激的中性粒细胞和抗ICAM 1对缺血的肾脏进行再灌注。缺血后，抗ICAM 1可预防离体肾脏再灌注损伤中的中性粒细胞成分。氧代谢产物已被证明可诱导内皮细胞表达ICAM 1。为了确定ICAM 1在氧化介导的肾损伤中的作用，用过氧化氢酶（CAT）对缺血的离体肾脏进行再灌注，并用过氧化氢对非缺血肾脏进行灌注。缺血后，用CAT再灌注可预防中性粒细胞潴留和损伤。在非缺血肾脏中，过氧化氢导致预激活的中性粒细胞潴留、激活和肾损伤，而抗ICAM 1可完全预防这些情况。
（1）缺血的肾脏会导致离体肾脏中的中性粒细胞潴留、激活和肾损伤加重；（2）中性粒细胞潴留取决于中性粒细胞的激活状态、肾脏缺血持续时间，并由氧代谢产物和ICAM 1介导。这种协同作用可能解释了在脓毒症等既有肾脏灌注不足又有中性粒细胞预激活的情况下ARF的高发生率。
