Arginase I expression and activity in human mononuclear cells after injury - PubMed (original) (raw)

Arginase I expression and activity in human mononuclear cells after injury

J B Ochoa et al. Ann Surg. 2001 Mar.

Abstract

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.

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Figures

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Figure 1. Peripheral blood mononuclear cell arginase activity. Peripheral blood samples from 17 trauma patients were collected daily from admission (day 0) to discharge from the intensive care unit (up to 7 days). Peripheral mononuclear cells were isolated by density gradient separation and arginase activity was measured. Each large box represents the 25th to 75th percentiles. Lines across large boxes show medians; small boxes show means. Whiskers at the top and bottom show upper and lower deciles, respectively. Arginase activity for the 20 controls is also.

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Figure 2. Human peripheral mononuclear cell arginase I protein expression. Peripheral leukocytes were isolated by density gradient from healthy volunteers (lanes 1–4) and from adult trauma victims 1 day after injury (lanes 5–8). Cell lysates were prepared and arginase I protein expression levels were determined by Western blot analysis (40 μg protein per lane). Samples from four representative controls and four trauma patients are shown. Human liver extract (1 μg) was used as a positive control.

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Figure 3. Postinjury changes in levels of selected amino acids. Plasma samples from trauma patients were collected daily from admission (day 0) to discharge from the intensive care unit (up to 7 days), and amino acids were measured. Values for the 20 controls are also shown.

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Figure 4. Peripheral blood samples from 17 trauma patients were collected daily from admission (day 0) to discharge from the intensive care unit (up to 7 days). Plasma was separated by centrifugation. Total nitrite and nitrate levels were measured by chemiluminescence. Each large box represents the 25th to 75th percentiles. Lines across large boxes show median; small dark boxes show means. Whiskers at the top and bottom show upper and lower deciles respectively. Nitrate + nitrate for the 20 controls are also shown.

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