Metabolism in the healing wound

Although glutamine is the most abundant free amino acid in the circulation, major physiologic stresses, such as surgery or sepsis, are sufficient to alter the balance significantly between net glutamine production and consumption. Animal studies by Kapadia et al. demonstrated that plasma and muscle glutamine levels may fall postoperatively by as much as 30 and 50% at 24 and 48 h, respectively [33]. Similarly, studies in patients undergoing major vascular operations showed that plasma glutamine concentrations diminished by 50% during the acute postoperative period [34]. This dramatic decline in circulating and muscle glutamine concentrations following major surgery exemplifies the increased demand for this amino acid by certain organ systems during stress.

Local Wound Healing

Wound healing is a complex cascade of events that occur on the cellular and molecular level in response to injury. Platelets, polymorphonuclear (PMN) leukocytes, macrophages, and fibroblasts are recognized as the chief cell types of the immune system that respond at the site of injury in order to carry out their individual functions. As described previously, glutamine is an important fuel source for these rapidly dividing cells and is necessary for DNA and RNA replication prior to mitosis. There is evidence that there are considerable amounts of glutaminase activity in the skin of mice and rats that allow these tissues to utilize glutamine as an energy source [35]. These researchers were also able to demonstrate that glutaminase activity in the skin of the animals decreased as they aged.

In an acute wound, fibroblasts appear on day three at the start of the proliferative phase and produce the permanent wound matrix. Fibroblasts replace the transient fibronectin-fibrin framework with collagen, which is essential to increase the tensile strength of the wound over time. Research on the metabolism of these important wound healing cells revealed that a-ketoglutarate, a metabolite of glutamine, is taken up by these cells by an unmediated diffusion process [36]. Moreover, these cells are able to utilize glutamine as an energy source instead of glucose [37]. Although early research indicated that glutamine supplementation had no appreciable effect on local wound healing [38], more recent studies have shown it may be efficacious. Volunteers (average age 75.4 yr) had small polytetrafluoroethylene (PTFE) grafts implanted subcutaneously and were either supplemented with a combination of glutamine, arginine, and P-hydroxy-P-methylbutyrate (HMB) or with isonitrogenous nonessential amino acids. The grafts removed at 2 weeks from the supplemented patient group showed a more significant amount of collagen deposition than did the nonsupple-mented group [39]. Because glutamine was given in combination with arginine and HMB, which have both been shown to increase collagen deposition, one cannot definitively conclude that glutamine promotes collagen deposition in vivo. However, in in vitro studies, it was shown that glutamine stimulates the synthesis of collagen in fibroblast cultures [40], and glutamine has a dose-dependent effect on collagen gene expression [41].

Gastrointestinal Tract

The cells lining the alimentary tract are particularly avid glutamine consumers, and utilization can increase markedly following surgery. Through animal studies, researchers have estimated that glutamine uptake by the canine gastrointestinal tract nearly doubles following surgery. This effect was subsequently shown to be related to the operative stress and not to a decrease in food intake [42]. Moreover, glutamine uptake by the gut is increased postoperatively despite reduced intestinal blood flow and diminished circulating plasma glutamine concentrations, suggesting that an active process for glutamine uptake independent of substrate delivery occurs. Glu-cocorticoid hormones elaborated in response to surgical stress have an integral role in regulating this uptake and determining the rate of consumption of glutamine by the gut. Administration of the glucocorticoid dexamethasone can reproduce the effects of laparotomy and more than double glutamine uptake in the canine gut through an increased extraction of the amino acid from the bloodstream [43]. Glutamine transported into the enterocyte is hydrolyzed by the enzyme glutaminase to generate glutamate and ammonia for a variety of cellular functions, including cellular respiration. Glucocorticoids also play an important regulatory role by increasing the intestinal mucosal glutaminase messenger RNA (mRNA) levels in a time-dependent manner [44]. It has been speculated that the increase in glutamine consumption by the gut during stress allows the gut to switch from an organ of glucose uptake to one of net release. This adaptation may increase available glucose for wound healing or for other tissues that are obligate glucose consumers. Furthermore, glutamine uptake in the gut supports alanine release for gluconeogenesis in the liver. Other mediators may also play a role in determining glutamine uptake and utilization in the gastrointestinal tract following surgical stress. The pancreatic hormone glucagon was also shown to increase intestinal glutamine uptake threefold as well as increase ammonia and decrease glutamine concentrations in the portal circulation [45].

The gut has received the most attention when evaluating the effects of glutamine supplementation. The importance of circulating glutamine in maintaining gut function and integrity was illustrated in a number of animal studies. In one study, the enzyme glutaminase was infused into several animal species to lower blood glutamine levels to nearly undetectable levels [46]. These animals rapidly developed diarrhea, mild villous atrophy, mucosal ulcerations, and intestinal necrosis. Likewise, Hwang et al. demonstrated that glutamine-enriched parenteral solutions increased jejunal mucosal weight and DNA content and significantly decreased the villous atrophy associated with the use of standard TPN [47]. Others have demonstrated the ability of glutamine-supplemented intravenous or enteral diets to increase villous height and mucosal nitrogen content and stimulate intestinal mucosal growth following starvation [48]. Furthermore, enteral or parenteral glutamine may offer some protection against aspirin-induced gastric ulcerations [49], peptic ulcer disease, and severe enteritis following chemotherapy and radiation therapy. Glutamine may also be useful in the treatment of infectious diarrhea, as indicated by Nath et al. who demonstrated that intestinal sodium absorption in diarrheogenic rabbits infected with Escherichia coli can be enhanced by administering enteral glutamine [50]. Frankel et al. showed that infusion of glutamine into the lumen of transplanted small intestine increased small bowel protein and glucose absorption [51].

Alverdy et al. initially reported that TPN promotes bacterial translocation in the rat intestine. However, when rats were infused with glutamine-enriched TPN, bacterial translocation was dramatically reduced. Glutamine-supplemented TPN was also associated with normalization of secretory immunoglobulin A levels compared to standard TPN [52]. Others have shown that glutamine-enriched TPN diminishes bacterial adherence to enterocytes while maintaining both B- and T-cell populations in the lamina propria of the terminal ileum [53]. Therefore the ability of glutamine to decrease bacterial translocation may be related to a combination of increased gut integrity and enhanced immune function.

Liver and Pancreas

The flow of glutamine into and out of the liver in surgical patients varies widely depending on the clinical scenario. Physiologic concentrations of ammonia in the portal circulation can produce "feed-forward stimulation" of hepatic glutaminase, allowing the liver to increase glutamine consumption when glutamine is abundant. Similarly, during starvation proinflammatory cytokines and eicosanoids can increase glutamine transport and utilization in the liver [54,55]. However, during metabolic acidosis glutamine flow is directed away from the liver and is significantly increased in the kidney. Under these conditions hepatic ureagenesis is decreased but renal ammoniagenesis is increased to facilitate net bicarbonate gain in the body. Gluco-corticoids and postoperative stress have also been shown to increase renal glutamine uptake. Because glucocorticoids, inflammatory cytokines, and acidosis may coincide with different levels in the surgical patient, the relative amounts of glutamine utilization by the liver and kidney can vary greatly between individuals.

Glutamine supports pancreatic growth and function during elemental enteral feeding as previously described. When isolated pancreatic islets were perfused with glutamine, the basal glucagon output was increased, and insulin production was diminished [56]. Alterations in the portal insulin-to-glucagon ratio can influence fatty infiltration of the liver. This observation was corroborated by the findings of Li et al., who showed that adult rats receiving standard TPN demonstrated panlobular vacuolation of hepatocytes on histology, while animals receiving glutamine-enriched TPN showed normal liver morphology [57]. These results suggested that in addition to supporting the numerous metabolic activities in the liver, nutritional glutamine may have a role in preventing hepatic steatosis.

Immune System

Glutamine is essential for optimal humoral and cell-mediated immune function, and tissue culture studies have demonstrated its requirement for in vitro lymphocyte function as described above. To examine the relation between glutamine depletion and lymphocyte and macrophage function in vivo, Parry-Billings et al. isolated lymphocytes from the blood of severely burned patients with profoundly low plasma glutamine levels [58]. Lymphocyte proliferation in response to antigenic stimulation in vitro was significantly limited under low media glutamine concentrations but increased as glutamine levels were restored to the normal plasma range. The implication of these studies is that the immunodeficiency which is so often encountered in the critically ill surgical patient may in part be related to decreased levels of glutamine. Furthermore, it suggests that at least part of this immunodeficiency may be amenable to therapy via glutamine-supplemented nutritional support.

Following surgical procedures or development of infection certain populations of immune cells, including neutrophils and macrophages, proliferate rapidly. Brand et al. demonstrated that glutamine utilization by proliferating thymocyte cells is tenfold greater than that by nonproliferating cells [59]. In addition, there is evidence that certain mediators, such as interleukin-1 (IL-1) and glucocorticoids, may augment lymphocyte glutaminase activity. Therefore it is reasonable to suggest that under traumatic stress conditions the immune system may increase its use of glutamine considerably.

Skeletal Muscle

Not all organ systems increase glutamine consumption in response to surgical stress. Skeletal muscle and the lungs, the principal organs of glutamine production, increase their output of glutamine into circulation following surgical procedures or other physiologic stress. Dual regulatory mechanisms, including systemic release of glu-cocorticoids and regional factors such as upregulation of glutamine synthetase activity, finely control glutamine production and meet glutamine demand during stress.

The accelerated muscle glutamine release that occurs after surgical stress can be profound. Muhlbacher et al. demonstrated that following treatment with the glucocorticoid dexamethasone, glutamine efflux was increased fourfold from the hindquarter muscles in a canine model [60]. Over a period of 9 d, the steroid-treated dogs developed muscle glutamine depletion and a negative nitrogen balance. Similar results were described in animals during sepsis, starvation, acidosis, and burn injury

[10,60]. Although glutamine comprises more than 50% of the total muscle amino acid pool, this does not fully account for the quantity of glutamine released following stress. Instead, glutamine must be synthesized de novo in muscle cells from glutamate and ammonia in a process catalyzed by glutamine synthetase. This can be upregulated tenfold in response to a septic challenge or direct glucocorticoid administration [61].

Depletion of the glutamine stores in skeletal muscle following major surgery is a well-recognized phenomenon. A statistically significant correlation between survival and muscle glutamine concentration has been demonstrated in septic patients [62]. Glutamine infusion during the postoperative period can diminish the efflux of glutamine from the hind limbs in a canine model and can lead to increased protein synthesis [33]. The impact of exogenous glutamine on protein synthesis was greatest when intramuscular glutamine concentrations fell to the range typically encountered during critical illness. Parenteral glutamine can also significantly diminish the muscle atrophy characteristic of chronic glucocorticoid exposure [63]. Hammarqvist et al. demonstrated that glutamine-enriched TPN decreased the fall in muscle glutamine concentration in patients undergoing cholecystectomy, preserved the total muscle ribosome concentration, and significantly limited the cumulative nitrogen loss compared to a control group [64]. Although muscle function appears to be relatively preserved even during moderate to severe glutamine depletion, the effects of decreased glutamine have systemic ramifications for morbidity and mortality within the critically ill patient population.

Lung

It was shown that the lung is an important source of glutamine during catabolic states. In addition to exportation, the lung is also a consumer of glutamine, particularly the endothelial surface. In a study examining the effects of glutamine infusion on lung weights after a bolus of endotoxin, researchers noted that there was more edema in endotoxin-treated animals that received a control amino acid infusion than in the glutamine-infused group [17]. Although the mechanism behind this phenomenon is not known, the role of glutamine in glutathione and taurine synthesis may be involved. It is possible that the lung may have increased ability to scavenge free radicals with glutathione and have increased osmoregulation via the activities of taurine. Additionally, glutamine supplementation significantly increased ATP levels and viability of pulmonary endothelial cells 5 h after hydrogen peroxide injury [65]. This suggests that glutamine may provide an important source of energy for the injured lung.

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