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Arginase I Expression and Activity in Human Mononuclear Cells After Injury

Ochoa, Juan B. MD*; Bernard, Andrew C. MD*; O’Brien, William E. PhD; Griffen, Margaret M. MD*; Maley, Mary E. BS*; Rockich, Anna K. PharmD*; Tsuei, Betty J. MD*; Boulanger, Bernard R. MD*; Kearney, Paul A. MD*; Morris, Sidney M. Jr. PhD

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Objective To determine the effect of trauma on arginase, an arginine-metabolizing enzyme, in cells of the immune system in humans.

Summary Background Data Arginase, classically considered an enzyme exclusive to the liver, is now known to exist in cells of the immune system. Arginase expression is induced in these cells by cytokines interleukin (IL) 4, IL-10, and transforming growth factor beta, corresponding to a T-helper 2 cytokine profile. In contrast, nitric oxide synthase expression is induced by IL-1, tumor necrosis factor, and gamma interferon, a T-helper 1 cytokine profile. Trauma is associated with a decrease in the production of nitric oxide metabolites and a state of immunosuppression characterized by an increase in the production of IL-4, IL-10, and transforming growth factor beta. This study tests the hypothesis that trauma increases arginase activity and expression in cells of the immune system.

Methods Seventeen severely traumatized patients were prospectively followed up in the intensive care unit for 7 days. Twenty volunteers served as controls. Peripheral mononuclear cells were isolated and assayed for arginase activity and expression, and plasma was collected for evaluation of levels of arginine, citrulline, ornithine, nitrogen oxides, and IL-10.

Results Markedly increased mononuclear cell arginase activity was observed early after trauma and persisted throughout the intensive care unit stay. Increased arginase activity corresponded with increased arginase I expression. Increased arginase activity coincided with decreased plasma arginine concentration. Plasma arginine and citrulline levels were decreased throughout the study period. Ornithine levels decreased early after injury but recovered by postinjury day 3. Increased arginase activity correlated with the severity of trauma, early alterations in lactate level, and increased levels of circulating IL-10. Increased arginase activity was associated with an increase in length of stay. Plasma nitric oxide metabolites were decreased during this same period.

Conclusions Markedly altered arginase expression and activity in cells of the human immune system after trauma have not been reported previously. Increased mononuclear cell arginase may partially explain the benefit of arginine supplementation for trauma patients. Arginase, rather than nitric oxide synthase, appears to be the dominant route for arginine metabolism in immune cells after trauma.

From the *Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky; the †Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas; and the ‡Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania

Supported by the National Institutes of Health (KO8-00676-01 [J.B.O.] and RO1-GM 57348 [S.M.M., W.E.O.]).

Correspondence: Juan B. Ochoa, MD, Section on Trauma and Critical Care, C222 Division of General Surgery, Department of Surgery, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536-0084.

E-mail: jochoa@pop.uky.edu

Accepted for publication August 7, 2000.

© 2001 Lippincott Williams & Wilkins, Inc.