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Acute Uremia but Not Renal Inflammation Attenuates Aseptic Acute Lung Injury: A Critical Role for Uremic Neutrophils

Alexander Zarbock^*,, Mirco Schmolke^*, Tilman Spieker, Kerstin Jurk^*, Hugo Van Aken^* and Kai Singbartl^*,

^* Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin; Institut für Pathologie, Universitätsklinikum Münster, Münster, Germany; Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; and Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Address correspondence to: Dr. Kai Singbartl, Department of Critical Care Medicine, University of Pittsburgh, 3550 Terrace Street, 613 Scaife Hall, Pittsburgh, PA 15261. Phone: 412-647-1473; Fax: 412-647-8060; singbartlk3{at}upmc.edu

Received for publication April 14, 2006. Accepted for publication August 22, 2006.

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 O₂ (>70%) in nonuremic mice. Uremic mice, by contrast, showed a significant protection from ALI (decrease in arterial partial pressure of O₂ <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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673