The central role of arginine catabolism in T-cell dysfunction and increased susceptibility to infection after physical injury.

OBJECTIVE: To explore the hypothesis that decreased arginine availability by myeloid-derived suppressor cells (MDSCs) is a cause of T-cell dysfunction after physical injury (PI). BACKGROUND: Arginine is an essential amino acid for normal T-cell function whose availability becomes limited after PI. MDSCs expressing arginase 1 are induced by PI. T-cell dysfunction after PI seems to increase the risk of infection but the mechanisms that cause it are unclear. METHODS: PI was created using a standard laparotomy model. Phenotypical and functional alterations in T cells were evaluated in vivo. MDSCs expressing arginase 1 were measured by flow cytometry. Infection after PI was created by intraperitoneal injection of Listeria monocytogenes. N-Hydroxy-Nor-L-arginine (Nor-NOHA) was used as an arginase inhibitor. The effect of arginine depletion on T-cell function and susceptibility to infection was assessed through adoptive transfer of MDSC or injection of arginase into noninjured mice. RESULTS: PI caused a decrease in intracellular arginine in T cells, loss of the T-cell receptor (TCR) CD3-ζ chain, inhibition of in vivo T-cell proliferation, memory, and cytotoxicity. PI exponentially increased bacterial growth and mortality to L. monocytogenes. T-cell dysfunction and increased infection were reversed by arginase inhibitor Nor-NOHA but were reproduced by adoptively transferring MDSC or injecting arginase 1 to noninjured mice. CONCLUSIONS: Arginine availability is decreased after PI coinciding with an induction of MDSC expressing arginase 1. Decreased arginine may inhibit T-cell function and increase susceptibility to infection after injury.

Arginine deficiency caused by myeloid cells: importance, identification and treatment.

Dietary arginine supplementation has been suggested as a means of improving T lymphocyte function and has found its greatest clinical utility in patients undergoing elective surgery. In other illnesses, arginine supplementation is controversial. Breakthroughs in understanding arginine metabolism have led to the identification of myeloid cells that express arginase 1, causing significant depletion of arginine - an essential amino acid for normal T lymphocyte function. Hence, myeloid cells expressing arginase 1 are also known as myeloid-derived suppressor cells. This chapter discusses the hypothesis that arginine replacement therapy may be necessary in arginine deficiency states.

Nutrition assessment and intervention in the patient with dysphagia: challenges for quality improvement.

Dysphagia, a symptom characterized by difficulty swallowing, is an independent predictor of poor outcome, worsening morbidity, increasing the risk for hospital readmissions, health care costs and mortality. Dysphagia is a result of a number of illnesses including neurological diseases, after surgery for head and neck pathology, observed in the intensive care unit after prolonged endotracheal intubation among others, and is particularly frequent in the elderly. Dysphagia increases the incidence of malnutrition, which in turn delays patient recovery. Treatment of dysphagia can be successful, but requires the use of multidisciplinary teams. A focus on the management of malnutrition including prevention and treatment is essential. Perhaps the biggest challenge is the lack of awareness of the presence of dysphagia and malnutrition, so that only a minority of patients are identified and successfully treated. We propose that better identification and treatment of dysphagia could occur with the systematic implementation of clinical practice improvement processes with a consequent decrease in morbidity, mortality and cost.

Immunonutrition for patients undergoing elective surgery for gastrointestinal cancer: impact on hospital costs.

BACKGROUND: Oral or enteral dietary supplementation with arginine, omega 3 fatty acids and nucleotides (known as immunonutrition) significantly improve outcomes in patients undergoing elective surgery. The objective of the study was to determine the impact on hospital costs of immunonutrition formulas used in patients undergoing elective surgery for gastrointestinal cancer. METHODS: US hospital costs of stay with and without surgical infectious complications, and average cost per day in the hospital for patients undergoing elective surgery for gastrointestinal cancer were estimated using data from the Healthcare Cost and Utilization Project's 2008 Nationwide Inpatient Sample. These costs were then used to estimate the impact of perioperative immunonutrition on hospital costs using estimates of reduction in infectious complications or length of stay from a meta-analysis of clinical trials in patients undergoing elective surgery for gastrointestinal cancer. Sensitivity of the results to changes in baseline complication rates or length of stay was tested. RESULTS: From the meta-analysis estimates, use of immunonutrition resulted in savings per patient of $3,300 with costs based on reduction in infectious complication rates or $6,000 with costs based on length of hospital stay. Cost savings per patient were present for baseline complication rates above 3.5% or when baseline length of stay and infectious complication rates were reduced to reflect recent US data for those with upper and lower GI elective cancer surgery (range, $1,200 to $6,300). CONCLUSIONS: Use of immunonutrition for patients undergoing elective surgery for gastrointestinal cancer is an effective and cost-saving intervention.

Outcomes of operative management of appendicitis.

BACKGROUND: There has not been an appraisal of outcomes of appendectomy for more than 10 years. More reliable diagnostic techniques and minimally invasive surgery are now in widespread use, yet the impact of these advances remains unknown. METHODS: A retrospective review was performed of 453 patients who underwent appendectomy for appendicitis at a single hospital from 2004 to 2009. Patient demographics, operative characteristics, procedure cost, and pathologic diagnoses were analyzed. RESULTS: The overall rate of complicated appendicitis was 13%, with a negative appendectomy rate of 4.9%. The average age was significantly greater for patients with complicated versus uncomplicated appendicitis (47 vs. 33 years, respectively; p<0.001), and by logistic regression, age (as a continuous variable) was a significant factor for complicated appendicitis (p<0.001). The hospital length of stay was 2.3 times longer for patients with complicated appendicitis (4.4 vs. 1.9 days; p<0.001), and the average cost was 86% higher ($14,125 vs. $7,595; p<0.001), the difference in cost being attributable mostly to pharmacy and nursing costs. CONCLUSIONS: Advances in diagnostic and surgical technique may be altering traditionally accepted rates of complicated appendicitis and negative appendectomy. For the first time, age is shown to be related to the rate of complicated appendicitis as a continuous variable rather than simply an extreme. Patients with complicated appendicitis still stay in the hospital longer, and there is a large cost difference as a result.

Systemic arginine depletion after a murine model of surgery or trauma.

BACKGROUND: Arginine metabolism and availability after surgery or trauma (ST) is an important modulator of immune responses. Arginine levels are significantly depleted in human trauma patients. Diets containing arginine administered to surgery patients have restored immune function. We hypothesized an arginase-dependent depletion of arginine in a murine model of ST. In addition, we hypothesized a systemic arginase release in human trauma patients. METHODS: Male mice were anesthetized and a laparotomy with bowel manipulation was used as a model of ST. Plasma was collected after ST for analysis of arginase activity and arginine, ornithine, and citrulline. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in plasma were measured after ST. Also, arginase activity was determined in human plasma from 4 healthy controls and 8 trauma patients. RESULTS: Arginase activity increased maximally at 2-4 hours after ST, and arginine was significantly reduced after ST. Citrulline was significantly decreased at 8 and 12 hours after ST. Plasma AST and ALT did not significantly vary from control mice after ST. In addition, on day 1 after intensive care unit admission, human trauma patients exhibited a significant increase in arginase activity. CONCLUSIONS: The biological consequences of arginine depletion remain incompletely understood. These data are consistent with data showing that patients given arginine-containing diets experience reduced morbidity. Understanding of arginine metabolism after ST may lead to therapies aimed at improving clinical outcome after ST.

Immunosupression and infection after major surgery: a nutritional deficiency.

T cell dysfunction significantly increases susceptibility to infections and organ failure after trauma or surgery (physical injury). This coincides with a persistent drop in arginine availability, a necessary amino acid for normal T cell function. Recent data led to the identification of a novel mechanism of T cell suppression caused by the depletion of arginine through the induction of arginase 1 (ARG1) in a specialized group of immature myeloid cells, now named myeloid-derived suppressor cells (MDSC). In addition to T cell dysfunction, arginine depletion leads to the decrease in nitric oxide (NO) production. Dietary therapy containing arginine at supraphysiologic concentrations along with other components such as omega-3 fat acids, antioxidants, nucleotides, and vitamin A is associated with improvement in T cell function, NO production, and a significant decrease in infection rates. The authors propose that a pathologic decrease in arginine availability is an identifiable nutrition deficiency syndrome that worsens outcomes if left untreated.

Deferred primary anastomosis versus diversion in patients with severe secondary peritonitis managed with staged laparotomies.

BACKGROUND: There is inconclusive data on whether critically ill individuals with severe secondary peritonitis requiring multiple staged laparotomies may became eligible candidates for deferred primary anastomoses (DPA). We sought to compare a protocol for DPA against a protocol for diversion in severely ill critical patients with intra-abdominal sepsis. METHODS: A retrospective cohort study was performed examining 112 patients admitted through an ICU between 2002 and 2006, with diagnosis of secondary peritonitis and managed with staged laparotomies whom required small- or large-bowel segment resections. Patients were categorized and compared according to the surgical treatment necessitated to resolve the secondary peritonitis (DPA versus diversion). Outcome measures were days on mechanical ventilation, days required in ICU, days required in hospital, incidence of fistulas/leakages, acute respiratory distress syndrome (ARDS), and mortality. RESULTS: There were 34 patients subjected to DPA and 78 to diversion. Fistulas/leakages developed in three patients (8.8%) with DPA and four patients (5.1%) with diversion (p = 0.359). ARDS was present in 6 patients (17.6%) with DPA and 24 patients (30.8%) with diversion (p = 0.149). There were 30 patients (88.2%) with DPA and 65 patients (83.3%) with diversion discharged alive (p = 0.51). There were not statistical significant differences between groups among survivors regarding hospital length of stay, ICU length of stay, and days on mechanical ventilation. CONCLUSIONS: We did not find significant differences in morbidity or mortality when we compared DPA versus diversion surgical treatment. It is feasible to perform a primary anastomosis in critically ill patients with severe secondary peritonitis managed with staged laparotomies.

Stat 6-dependent induction of myeloid derived suppressor cells after physical injury regulates nitric oxide response to endotoxin.

OBJECTIVE: To delineate the role of T-helper 2 (Th2) cytokines in the induction of trauma induced myeloid suppressor cells (TIMSC) and the regulation of nitric oxide production. BACKGROUND: Trauma induces myeloid cells that express CD11b+/Gr1+ and arginase 1 and exhibit an immune suppressing activity. This article explores the mechanisms that induce TIMSC and the effects on nitric oxide production in response to endotoxin. METHODS: TIMSC were studied in response to Th2 cytokines and a subsequent challenge to endotoxin. The role of Th2 cytokines was studied in STAT6-/- mice. Accumulation of TIMSC in spleens was studied using flow cytometry and immunhistochemistry. Plasma was recovered to measure accumulation of nitric oxide metabolites. RESULTS: TIMSC accumulated in the spleen of injured mice and were particularly sensitive to IL-4 and IL-13 with large inductions of arginase activity. Significant blunting in both the accumulation of TIMSC in the spleen and induction of arginase 1 was observed in STAT6-/- mice after physical injury. Accumulation of nitric oxide metabolites to endotoxin was observed in STAT6-/- mice. CONCLUSION: This study shows that induction of CD11b+/Gr1+ cells after physical injury play an essential role in the regulation of nitric oxide production after a septic challenge. The accumulation and induction of arginase 1 in TIMSC is Th2 cytokine dependent. To our knowledge, the role of TIMSC in the regulation of nitric oxide is a novel finding. This observation adds to the possibility that TIMSC could play an important role in immunosuppression observed after physical injury.

Hepatic resection in the management of complex injury to the liver.

BACKGROUND: Nonoperative management has become the standard for >80% of the blunt liver injuries. In the cases where operation is required, current operative management emphasizes packing, damage control, and early utilization of interventional radiology for angiography and embolization. Liver resection is thought to have minimal role in the management of hepatic injury because of the high morbidity and mortality in many reports. The objective of this study was to show that the management of complex liver injuries with anatomic or nonanatomic resection can be accomplished by experienced trauma surgeons, in conjunction with liver surgeons in some cases, with low morbidity and mortality related to the procedure. Delayed, planned anatomic resection was also applied. METHODS: This is a retrospective, observational study, on patients admitted to the University of Pittsburgh Medical Center (UPMC)-Presbyterian from December 1986 through March 2001. The patients included in this report underwent hepatic resection for complex liver injuries (grade 3, 4, and 5) according to the American for Association the Surgery of Trauma-Organ Injury Scale. Age, sex, mechanism of trauma, type of resection (nonanatomic, segmentectomy, lobectomy, and hepatectomy), surgical complications, hospital length of stay, and mortality were the variables analyzed. RESULTS: Two hundred sixteen adult patients were admitted with complex liver injury, during the period of December 1986 to March 2001. Fifty-six patients of this series underwent liver resection: 21 anatomic segmentectomies, 23 nonanatomic resections, 3 left lobectomies, 8 right lobectomies, and 1 hepatectomy with orthotopic liver transplant. The median age was 31 years (range, 15-83 years). The Injury severity Score average was 34 +/- 10 (range, 16-59). Mechanism was blunt in 62.5% and penetrating in 37.5%. The grades of hepatic injury were 9 grade III, 32 grade IV, and 15 grade V. A total of 28.5% (16 of 56) of patients had concomitant hepatic venous injury. The overall morbidity was 62.5%. The morbidity related to liver resection was 30%. The overall mortality of the series was 17.8%. Mortality from liver injury was 9% in this series of patients undergoing liver resection for complex hepatic injury. CONCLUSIONS: This study demonstrates that liver resection should be considered as a surgical option in patients with complex injury, as initial or delayed management, and can be accomplished with low mortality and liver related morbidity.

Effect of citrulline and glutamine on nitric oxide production in RAW 264.7 cells in an arginine-depleted environment.

BACKGROUND: Nitric oxide (NO) is a highly reactive free radical essential for antimicrobial and tumor immunity as well as endothelial function. Arginine is a limiting factor in NO synthesis. Citrulline can be converted to arginine and might restore NO production when arginine availability is limited, while glutamine may competitively inhibit citrulline availability. We aimed to assess how these amino acids interact to generate NO using an in vitro model. METHODS: RAW 264.7 cells were exposed to various amino acid concentrations before and after lipopolysaccharide (LPS) stimulation, and NO production was assessed. RESULTS: NO production directly correlated up to 200 microM with arginine available after LPS stimulation (R(2) = 0.99). Provided the same arginine concentrations following LPS stimulation, low arginine precultured cells produced significantly less NO than high arginine precultured cells (P < .01). Citrulline added to low arginine preculture significantly increased NO production compared to cells in low arginine alone (P < .01). When glutamine was withdrawn before and after LPS stimulation, cells precultured in low arginine and citrulline produced NO equivalent to that of high arginine precultured cells. Additional citrulline provided after LPS stimulation additionally improved NO production beyond that observed in cells precultured in high arginine (P < .01), and NO production became less dependent on arginine availability (R(2) = 0.78). CONCLUSION: Arginine availability is a limiting factor for NO production. Citrulline is a potential substitute to restore NO production when arginine availability is limited. Glutamine appears to be an important modulator that interferes with citrulline-mediated NO production.

MRI is unnecessary to clear the cervical spine in obtunded/comatose trauma patients: the four-year experience of a level I trauma center.

BACKGROUND: Cervical (C)-spine clearance protocols exist both to identify traumatic injury and to expedite rigid collar removal. Computed tomography (CT) of the C-spine in trauma patients facilitates the removal of immobilization collars in patients who are neurologically intact, and magnetic resonance imaging (MRI) has become an indispensable adjunct for evaluating trauma patients with neurologic deficits. Yet, the management of patients with impaired mental status who lack neurologic deficits attributable to the spinal cord remains controversial. C-spine MRI has been suggested and employed as an imaging modality to exclude occult C-spine instability in this population of patients. However, currently available data are inconclusive as to the necessity of MRI in the C-spine clearance of obtunded or comatose trauma patients with a normal CT. METHODS: The records of patients undergoing contemporaneous CT and MRI of the C-spine in a level I trauma center from January 2003 to December 2006 were retrospectively analyzed. From this group, patients admitted with a Glasgow Coma Scale score

Arginine and immunity.

For many years, dietary arginine supplementation, often combined with other substances, has been used as a mechanism to boost the immune system. Considerable controversy, however, exists as to the benefits and indications of dietary arginine due in part to a poor understanding of the role played by this amino acid in maintaining immune function. Emerging knowledge promises to clear this controversy and allow for arginine's safe use. In myeloid cells, arginine is mainly metabolized either by inducible nitric oxide (NO) synthases (iNOS) or by arginase 1, enzymes that are stimulated by T helper 1 or 2 cytokines, respectively. Thus, activation of iNOS or arginase (or both) reflects the type of inflammatory response in a specific disease process. Myeloid suppressor cells (MSC) expressing arginase have been described in trauma (in both mice and humans), intra-abdominal sepsis, certain infections, and prominently, cancer. Myeloid cells expressing arginase have been shown to accumulate in patients with cancer. Arginase 1 expression is also detected in mononuclear cells after trauma or surgery. MSC efficiently deplete arginine and generate ornithine. Through arginine depletion, MSC may control NO production and regulate other arginine-dependent biological processes. Low circulating arginine has been documented in trauma and cancer, suggesting that MSC may exert a systemic effect and cause a state of arginine deficiency. Simultaneously, T lymphocytes depend on arginine for proliferation, zeta-chain peptide and T-cell receptor complex expression, and the development of memory. T-cells cocultured with MSC exhibit the molecular and functional effects associated with arginine deficiency. Not surprisingly, T-cell abnormalities, including decreased proliferation and loss of the zeta-chain, are observed in cancer and after trauma.

Evaluation of a 15-year experience with splenic injuries in a state trauma system.

BACKGROUND: The management of splenic injuries has evolved with a greater emphasis on nonoperative management. Although several institutions have demonstrated that nonoperative management of splenic injuries can be performed with an increasing degree of success, the impact of this treatment shift on outcome for all patients with splenic injuries remains unknown. We hypothesized that outcomes for patients with splenic injuries have improved as the paradigm for splenic injury treatment has shifted. METHODS: Consecutive patients from 1987 to 2001 with splenic injuries who were entered into a state trauma registry were reviewed. Demographic variables, injury characteristics, and outcome data were collected. RESULTS: The number of patients who were diagnosed with splenic injuries increased from 1987 through 2001, despite a stable number of institutions submitting data to the registry. The number of minor injuries and severe splenic injuries remained stable, and the number of moderately severe injuries significantly increased over time. Overall mortality rate improved but primarily reflected the decreased mortality rates of moderately severe injuries; the mortality rate for severe splenic injuries was unchanged. CONCLUSION: Trauma centers are seeing increasing numbers of splenic injuries that are less severe in magnitude, although the number of the most severe splenic injuries is stable. The increased proportion of patients with less severe splenic injuries who are being admitted to trauma centers is a significant factor in the increased use and success rate of nonoperative management.

CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress.

T cell dysfunction that occurs after surgery or trauma is associated with a poor clinical outcome. We describe that myeloid suppressor cells expressing CD11b(+)/Gr-1(+) markers invade the spleen after traumatic stress and suppress T cell function through the production of arginase 1. We created a consistent model of traumatic stress in C57BL/6 mice to perform this work. A significant number of CD11b(+)/Gr-1(+) cells expressing arginase 1 accumulated in T cell zones around the germinal centers of the white pulp of the spleen within 6 h of trauma and lasted for at least 72 h. Increased arginase activity and arginase 1 expression, along with increased [(3)H]arginine uptake, l-arginine depletion, and l-ornithine accumulation in the culture medium, were observed exclusively in CD11b(+)/Gr-1(+) cells after traumatic stress. Flow cytometry revealed CD11b(+)/Gr-1(+) as a heterogeneous myeloid suppressor cell also expressing low levels of MHC class I and II, CD80, CD86, CD31, and others. When compared with controls, trauma-induced CD11b(+)/Gr-1(+) cells significantly inhibited CD3/CD28-mediated T cell proliferation, TCR zeta-chain expression, and IL-2 production. The suppressive effects by trauma CD11b(+)/Gr-1(+) cells were overcome with the arginase antagonist N-hydroxy-nor-l-arginine or extrasupplementation of medium with l-arginine. Poor Ag-presenting capacity of control and trauma-induced CD11b(+)/Gr-1(+) cells was detected in allogeneic murine leukocyte reaction. This study demonstrates that CD11b(+)/Gr-1(+) cells invade the spleen following traumatic stress and cause T cell dysfunction by an arginase-mediated mechanism, probably that of arginine depletion. Understanding the mechanism of immune suppression by these cells has important clinical implications in the treatment of immune dysfunction after trauma or surgery.

Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma.

Myeloid suppressor cells (MSCs) producing high levels of arginase I block T cell function by depleting l-arginine in cancer, chronic infections, and trauma patients. In cancer, MSCs infiltrating tumors and in circulation are an important mechanism for tumor evasion and impair the therapeutic potential of cancer immunotherapies. However, the mechanisms that induce arginase I in MSCs in cancer are unknown. Using the 3LL mouse lung carcinoma, we aimed to characterize these mechanisms. Arginase I expression was independent of T cell-produced cytokines. Instead, tumor-derived soluble factors resistant to proteases induced and maintained arginase I expression in MSCs. 3LL tumor cells constitutively express cyclooxygenase (COX)-1 and COX-2 and produce high levels of PGE2. Genetic and pharmacological inhibition of COX-2, but not COX-1, blocked arginase I induction in vitro and in vivo. Signaling through the PGE2 receptor E-prostanoid 4 expressed in MSCs induced arginase I. Furthermore, blocking arginase I expression using COX-2 inhibitors elicited a lymphocyte-mediated antitumor response. These results demonstrate a new pathway of prostaglandin-induced immune dysfunction and provide a novel mechanism that can help explain the cancer prevention effects of COX-2 inhibitors. Furthermore, an addition of arginase I represents a clinical approach to enhance the therapeutic potential of cancer immunotherapies.

Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses.

T cells infiltrating tumors have a decreased expression of signal transduction proteins, a diminished ability to proliferate, and a decreased production of cytokines. The mechanisms causing these changes have remained unclear. We demonstrated recently that peritoneal macrophages stimulated with interleukin 4 + interleukin 13 produce arginase I, which decreases the expression of the T-cell receptor CD3zeta chain and impairs T-cell responses. Using a 3LL murine lung carcinoma model we tested whether arginase I was produced in the tumor microenvironment and could decrease CD3zeta expression and impair T-cell function. The results show that a subpopulation of mature tumor-associated myeloid cells express high levels of arginase I, whereas tumor cells and infiltrating lymphocytes do not. Arginase I expression in the tumor was seen on day 7 after tumor injection. Tumor-associated myeloid cells also expressed high levels of cationic amino acid transporter 2B, which allowed them to rapidly incorporate L-Arginine (L-Arg) and deplete extracellular L-Arg in vitro. L-Arg depletion by tumor-associated myeloid cells blocked the re-expression of CD3zeta in stimulated T cells and inhibited antigen-specific proliferation of OT-1 and OT-2 cells. The injection of the arginase inhibitor N-hydroxy-nor-L-Arg blocked growth of s.c. 3LL lung carcinoma in mice. High levels of arginase I were also found in tumor samples of patients with non-small cell carcinoma. Therefore, arginase I production by mature myeloid cells in the tumor microenvironment may be a central mechanism for tumor evasion and may represent a target for new therapies.

Regulation of arginase expression by T-helper II cytokines and isoproterenol.

BACKGROUND: Trauma causes a release of catecholamines, transforming growth factor-beta (TGF-beta), and T-helper II cytokines (TH2). Individually, these substances also induce arginase in macrophages. The purpose of this study was to determine the synergistic interactions between isoproterenol, TGF-beta, and TH2 cytokines on arginase expression in macrophages. METHODS: Confluent RAW 264.7 macrophages were incubated with various combinations of interleukins 4, 10, and 13 (IL-4, IL-10, IL-13), and TGF-beta with isoproterenol over 48 hours. Arginase activity, as well as arginase I expression by Western blot and reverse transcriptase-polymerase chain reaction, were measured. RESULTS: Although isoproterenol, IL-4, IL-10, and IL-13 individually induced arginase, significant synergy between the combination of isoproterenol with either TGF-beta or the TH2 cytokines was observed. All cytokines except IL-10 also induced arginase I protein and mRNA. Arginase II protein was detected in cells exposed to IL-10. CONCLUSIONS: We conclude that isoproterenol synergizes with IL-4, IL-13, and TGF-beta to increase arginase I mRNA and protein, as well as arginase activity in RAW 264.7 macrophages. Further, IL-10 synergizes with isoproterenol to increase arginase activity and arginase II protein. These synergistic mechanisms may compete with nitric oxide synthase for l-arginine substrate, thus shunting away available arginine from nitric oxide production and contributing to cellular immunosuppression observed after trauma.

A rational use of immune enhancing diets: when should we use dietary arginine supplementation?

Controversies in any arena of human activity often result in the polarization of the individuals involved into 2 opposing camps. Controversy about the use of immune-enhancing diets (IEDs) is no exception. On one hand, some groups are proposing indiscriminate use of IEDs, whereas others have created guidelines advocating that their use should be banned for the critically ill. At stake is an emerging paradigm: that dietary manipulation of the immune system is possible and may become an important adjunct to other therapies, thus helping prevent or treat multiple diseases for millions worldwide. Under these circumstances, extremist claims of miraculous benefits or inappropriate assertions of evil can only delay the emergence of a nascent science. This paper is therefore a plea for moderation from both camps, lest we cause irreparable damage to our clinical practices and potential injury to individual patients. IEDs all contain arginine. However, they also contain other substances such as omega-3 fatty acids, and nucleotides. The use of all these nutrients together into commercial IEDs without adequate evaluation of their individual effects has prevented the development of mechanistic hypotheses of action. Despite this, IEDs have been tested extensively, allowing the development of guidelines for their use. IEDs should be used for surgical patients, especially those undergoing elective surgery. IEDs show no benefit and indeed can potentially harm patients with sepsis, especially in the nonsurgical group, and should not be used outside of research protocols. Advances in basic research have helped us understand mechanisms of how arginine contained in IEDs may help surgical patients but may be deleterious in patients with sepsis. A review of the basic mechanisms of action of arginine on the immune system is enclosed in this paper and should serve as a basis for the development of scientific principles that guide clinical use of IEDs.

L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes.

L-Arginine plays a central role in the normal function of several organs including the immune system. It is metabolized in macrophages by inducible nitric oxide synthase to produce nitric oxide, important in the cytotoxic mechanisms, and by arginase I (ASE I) and arginase II (ASE II) to synthesize L-ornithine and urea, the first being the precursor for the production of polyamines needed for cell proliferation. L-Arginine availability can modulate T cell function. Human T cells stimulated and cultured in the absence of L-arginine lose the expression of the TCR zeta-chain (CD3zeta) and have an impaired proliferation and a decreased cytokine production. The aim of this work was to test whether activated macrophages could modulate extracellular levels of L-arginine and alter T cell function, and to determine which metabolic pathway was responsible for this event. The results show that macrophages stimulated with IL-4 + IL-13 up-regulate ASE I and cationic amino acid transporter 2B, causing a rapid reduction of extracellular levels of L-arginine and inducing decreased expression of CD3zeta and diminished proliferation in normal T lymphocytes. Competitive inhibitors of ASE I or the addition of excess L-arginine lead to the re-expression of CD3zeta and recovery of T cell proliferation. In contrast, inducible nitric oxide synthase or ASE II failed to significantly reduce the extracellular levels of L-arginine and modulate CD3zeta expression. These results may provide new insights into the mechanisms leading to T cell dysfunction and the down-regulation of CD3zeta in cancer and chronic infectious diseases.