Zarbock Alexander, Schmolke Mirco, Spieker Tilman, Jurk Kerstin, Van Aken Hugo, Singbartl Kai
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Münster, Münster, Germany.
J Am Soc Nephrol. 2006 Nov;17(11):3124-31. doi: 10.1681/ASN.2006040358. Epub 2006 Oct 11.
Acute renal failure (ARF) remains a major clinical challenge, especially in the intensive care setting. Mortality of ARF combined with acute lung injury (ALI) is even higher and may reach 80%. Recent studies have suggested a remote effect of ARF on pulmonary homeostasis. However, it is unknown whether and to what extent ARF clinically affects pulmonary function, in particular oxygenation. For elucidation of the impact of ARF on aseptic ALI, a murine two-hit model that consists of acute uremia (AU) and subsequent ALI was developed. AU was induced by renal ischemia-reperfusion (inflammatory AU) or bilateral nephrectomy (noninflammatory AU). ALI was initiated by intratracheal HCl instillation and characterized by severe, PMN-dependent decrease in arterial partial pressure of O(2) (>70%) in nonuremic mice. Uremic mice, by contrast, showed a significant protection from ALI (decrease in arterial partial pressure of O(2) <40%); this was independent of the type of AU. Reconstitution experiments, in which uremic neutrophils were injected into nonuremic mice and vice versa, identified uremic neutrophils as the primary mediators. Between normal and uremic neutrophils, there were no differences in apoptosis or superoxide production. Pulmonary recruitment of uremic neutrophils, however, was significantly attenuated compared with that of normal neutrophils. This defect was associated with altered surface expression of L-selectin; sialyl Lewis(x), an L-selectin counterreceptor, previously was proved to be critical in aseptic ALI. In conclusion, it is shown that AU but not renal inflammation attenuates aseptic, neutrophil-dependent ALI and exerts an anti-inflammatory effect by attenuating pulmonary neutrophil recruitment.
急性肾衰竭（ARF）仍然是一项重大的临床挑战，尤其是在重症监护环境中。ARF合并急性肺损伤（ALI）的死亡率更高，可能达到80%。最近的研究表明ARF对肺稳态有远程影响。然而，ARF在临床上是否以及在多大程度上影响肺功能，特别是氧合作用，尚不清楚。为了阐明ARF对无菌性ALI的影响，建立了一种由急性尿毒症（AU）和随后的ALI组成的小鼠双打击模型。AU通过肾缺血再灌注（炎症性AU）或双侧肾切除术（非炎症性AU）诱导。ALI通过气管内滴注HCl启动，其特征是在非尿毒症小鼠中动脉血氧分压严重下降（>70%），且依赖于中性粒细胞。相比之下，尿毒症小鼠对ALI有显著的保护作用（动脉血氧分压下降<40%）；这与AU的类型无关。重建实验将尿毒症中性粒细胞注入非尿毒症小鼠，反之亦然，结果确定尿毒症中性粒细胞是主要介质。正常中性粒细胞和尿毒症中性粒细胞在凋亡或超氧化物产生方面没有差异。然而，与正常中性粒细胞相比，尿毒症中性粒细胞在肺部的募集明显减弱。这种缺陷与L-选择素的表面表达改变有关；唾液酸化路易斯（x），一种L-选择素的反受体，先前已被证明在无菌性ALI中至关重要。总之，研究表明AU而非肾脏炎症可减轻无菌性、依赖中性粒细胞的ALI，并通过减弱肺部中性粒细胞募集发挥抗炎作用。
