Acute Renal Failure in Ards

Linas, Stuart L.

Abstract

Acute renal failure occurs late in the course and is a major cause of death in patients with acute edematous lung injury (ARDS). The mechanism by which the kidney is damaged in ARDS is unknown Recent evidence suggests that activated neutrophils and endotoxin, which are present in the blood of patients with ARDS, are important mediators of cell injury. The present hypothesis is that compared to the lung, the kidney is relatively resistant to injury by complement, endotoxin and/or neutrophils unless a preceding or superimposed ischemia/reperfusion insult has also occurred. Ischemia/reperfusion worsens injury by endotoxin and.or neutrophils by causing release of xanthine oxidase derived oxygen metabolites by he kidney which can directly injure kidney cells and predispose kidney cells to activated neutrophils by depleting cells of endogenous oxygen metabolite scavengers, enhancing neutrophil recruitment and inactivating circulation antiproteases. The preliminary data support this hypothesis. Blood levels of complement. endotoxin and neutrophils are increased in patients with ASRDS. In isolated perfused kidneys, neutrophils do not cause renal injury unless first activated by stimulators such as phorbol myristate acetate. Severe ischemia/reperfusion insults to kidneys cause neutrophils recruitment and neutrophils worsen ischemia.reperfusion injury in kidneys undergoing reperfusion after severe ischemic insults. The immediate specific objectives are to determine: 1) the effect of endotoxin, activated complement components and/or neutrophils alone and/or in combination on the structure and functions of the isolated perfused kidney; and 2) the effect of mild ischemia/reperfusion insults on the development of renal in injury in kidneys perfused with endoxotin, activated complement components and/or neutrophils. The significance of these studies is to improve understanding of mechanisms of kidney injury in ARDS. This new information may also be relevant to understanding the mechanisms by which ischemia/reperfusion predisposes to many other nephrotoxins, including antibiotics, anti-tumor drugs, hemoglobin and myoglobin.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Heart, Lung, and Blood Institute (NHLBI)
• Type: Specialized Center (P50)
• Project #: 5P50HL040784-03
• Application #: 3859534
• Support Year: 3
• Fiscal Year: 1991

Institution

• Name: University of Colorado Denver
• DUNS #: 065391526
• City: Aurora
• State: CO
• Country: United States
• Zip Code: 80045

Publications

Moore, Frederick A (2010) Presidential address: imagination trumps knowledge. Am J Surg 200:671-7

Hybertson, Brooks M; Chung, Jin H; Fini, Mehdi A et al. (2005) Aerosol-administered alpha-tocopherol attenuates lung inflammation in rats given lipopolysaccharide intratracheally. Exp Lung Res 31:283-94

Moss, Marc; Parsons, Polly E; Steinberg, Kenneth P et al. (2003) Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock. Crit Care Med 31:869-77

Hybertson, Brooks M; Jepson, Eric K; Allard, Jenny D et al. (2003) Transforming growth factor beta contributes to lung leak in rats given interleukin-1 intratracheally. Exp Lung Res 29:361-73

Gao, Bifeng; Flores, Sonia C; Leff, Jonathan A et al. (2003) Synthesis and anti-inflammatory activity of a chimeric recombinant superoxide dismutase: SOD2/3. Am J Physiol Lung Cell Mol Physiol 284:L917-25

Nick, Jerry A; Young, Scott K; Arndt, Patrick G et al. (2002) Selective suppression of neutrophil accumulation in ongoing pulmonary inflammation by systemic inhibition of p38 mitogen-activated protein kinase. J Immunol 169:5260-9

Lee, Young M; Hybertson, Brooks M; Cho, Hyun G et al. (2002) Platelet-activating factor induces lung inflammation and leak in rats: hydrogen peroxide production along neutrophil-lung endothelial cell interfaces. J Lab Clin Med 140:312-9

Suratt, B T; Young, S K; Lieber, J et al. (2001) Neutrophil maturation and activation determine anatomic site of clearance from circulation. Am J Physiol Lung Cell Mol Physiol 281:L913-21

Avdi, N J; Nick, J A; Whitlock, B B et al. (2001) Tumor necrosis factor-alpha activation of the c-Jun N-terminal kinase pathway in human neutrophils. Integrin involvement in a pathway leading from cytoplasmic tyrosine kinases apoptosis. J Biol Chem 276:2189-99

Moss, M; Guidot, D M; Steinberg, K P et al. (2000) Diabetic patients have a decreased incidence of acute respiratory distress syndrome. Crit Care Med 28:2187-92