Glutamine Administration in Early or Late Septic Phase Downregulates Lymphocyte PD‐1/PD‐L1 Expression and the Inflammatory Response in Mice With Polymicrobial Sepsis

Background: Sepsis is a severe inflammatory response to infection. Excessive compensation to inflammation leads to dysregulated immune response that ultimately results in organ damage and lethality of sepsis. This study administered glutamine (GLN) in the early or late phase of sepsis to investigate its effects on regulating leukocyte programmed cell death 1 (PD‐1) and its ligand (programmed cell death ligand 1 [PD‐L1]) expression, macrophage function, inflammation, and acute kidney injury in sepsis. Methods: Mice were randomly assigned to cecal ligation and puncture (CLP) or sham‐operated groups. Septic mice were respectively injected once with saline or 0.75 g GLN/kg body weight at 3 or 10 hours post‐CLP via tail vein. All mice were sacrificed 24 hours after CLP. Results: Sepsis enhanced the percentage of interferon‐γ–expressing and interleukin (IL)‐17A–expressing CD4⁺ T cells, expression of PD‐1 on T cells, and PD‐L1 on B cells and monocytes. Inflammatory mediator messenger RNA (mRNA) expression in kidney tissues and proapoptotic caspase‐3 mRNA expression in mesenteric lymph nodes were also upregulated. GLN administration decreased plasma IL‐6 level, downregulated the percentage of IL‐17A–expressing CD4⁺ T cells, attenuated macrophage dysfunction, decreased caspase‐3 mRNA expression, and reduced PD‐1/PD‐L1 expression by T and B cells. Histological findings also showed that kidney damage was attenuated. GLN administered at 3 and 10 hours after CLP offered nearly equal effects on PD‐1/PD‐L1 and inflammatory mediator expression after CLP. Conclusions: These findings suggest that a single dose of GLN administration in either the early or late phase during sepsis promotes a more balanced immune regulation and reduced systemic and kidney inflammatory responses in mice.     

Glutamine restores myocardial cytochrome C oxidase activity and improves cardiac function during experimental sepsis

Background: Cardiac dysfunction occurs commonly in sepsis. Impaired mitochondrial function is a potential cause of sepsis‐associated myocardial depression. Cytochrome oxidase (COX), the terminal oxidase of the electron transport chain, is inhibited in the septic heart. Glutamine (GLN) increases Krebs cycle intermediates and supports oxidative phosphorylation. Exogenous GLN has been shown to restore myocardial adenosine triphosphate levels and cardiac function following ischemia–reperfusion injury. The authors hypothesize that exogenous GLN will abrogate sepsis‐induced myocardial COX inhibition and improve sepsis‐associated myocardial depression. Methods: Under general anesthesia, male Sprague‐Dawley rats underwent cecal ligation and double puncture (CLP) or sham operation. At the time of operation, rats underwent intraperitoneal injection of either GLN (0.75 g/kg) or an equal volume of saline. Twenty‐four hours after the procedure, animals were killed, cardiac ventricles harvested, and mitochondria isolated. Steady‐state COX kinetic activity was measured and normalized to citrate synthase activity. Steady‐state levels of COX subunit I protein were determined with immunoblot analysis. Cardiac function was assessed using an isolated rat heart preparation. Five animals per group were evaluated. Significance was determined with analysis of variance and post hoc Tukey test. Results: CLP significantly decreased myocardial COX activity, oxygen consumption, left ventricular pressure (LVP), and pressure developed during isovolumic contraction (+dP/dt) and relaxation (?dP/dt). GLN restored COX activity to sham levels, significantly increased myocardial oxygen extraction and consumption, increased LVP toward sham values, and increased ±dP/dt by >30% following CLP. Conclusion: The beneficial effects of GLN therapy during sepsis may be in part due to restoration of oxidative phosphorylation and abrogation of sepsis‐associated myocardial depression.     

Oral and parenteral glutamine in bone marrow transplantation: a randomized, double-blind study.

BACKGROUND: Total parenteral nutrition (TPN) supplemented with glutamine (GLN) has been reported to be effective for patients with bone marrow transplantation (BMT). Our aim was to evaluate enteral and parenteral glutamine in patients undergoing BMT. METHODS: For evaluation of GLN in BMT, 66 patients with 43 hematologic and 23 solid malignancies (21 breast carcinomas), were randomized, double-blinded, to either oral GLN (n = 35) or glycine-control (GLY) (n = 31), 10 g three times daily. When TPN became necessary, patients who received GLN orally were given TPN with GLN (0.57 g/kg). Those who received GLY received standard TPN, isocaloric and isonitrogenous. Patients with hematologic malignancies received high-dose chemotherapy, total body irradiation, and either allogeneic (ALLO) BMT (n = 18) or autologous (AUTO) stem cell transplantation (n = 25). Patients with solid malignancies (n = 23) received AUTO. RESULTS: There were 14 in-hospital deaths without relationship to GLN administration. For respective comparisons of ALLO and AUTO transplants in the GLN and GLY hematologic groups and AUTO in the solid tumor groups, there were no significant differences in hospital stay, duration of stay after BMT, TPN days, neutrophil recovery >500/mm3, incidence of positive blood cultures, sepsis, mucositis, and diarrhea. Acute graft us host disease occurred in 1 of 10 hematologic patients receiving GLN and in 3 of 8 patients receiving GLY placebo (p > .05). Possible reduction in need for TPN and a suggestion of improved long-term survival were associated with GLN. CONCLUSIONS: Oral and parenteral GLN seemed to be of limited benefit for patients having AUTO or ALLO BMT for hematologic or solid malignancies. Further study of long-term effects of GLN in BMT seems warranted.     

Effect of Glutamine on Gut Glutathione Fractional Release in the Implanted Tumor Model

Cancer and its treatments cause a marked depletion of glutamine (GLN). However, dietary GLN can restore this loss and improve the outcomes of the treatments. The reasons behind this need to be investigated. GLN is suggested to involve in glutathione (GSH) synthesis. Fast-growing tumors alter gut GLN metabolism, but the effect of tumor growth on gut GSH release remains unknown. We hypothesized that gut GSH release would decrease in the tumor-bearing host and this downregulation would be antagonized by supplemental GLN. Female Fisher-344 rats were randomized to the groups: GLN + TUMOR, Freamine (FA) + TUMOR, GLN + SHAM, and FA + SHAM. The rats were implanted with MTF-7 mammary tumors as tumor-bearing groups, whereas the rats were sham operated as control groups. The rats were pair fed chow, gavaged with 1 g/kg/day GLN or an isonitrogenous FA. Tumor growth, blood and gut mucosa GLN, glutamate, and/or GSH were measured. The gut extractions, defined as the difference of concentrations across the gut, were calculated. Supplemental GLN enhanced the gut GLN uptake and GSH release with tumor growth and significantly increased blood and gut mucosa GLN and/or GSH concentrations. Our results demonstrate the important antioxidant role of GLN and thus may have significant implications in nutritional immune modulation in cancer patients.     

Effects of oral supplementation with glutamine and alanyl-glutamine on glutamine,glutamate, and glutathione status in trained rats and subjected to long-duration exercise

ObjectiveWe investigated the effect of supplementation with the dipeptide L-alanyl-L-glutamine (DIP) and a solution containing L-glutamine and L-alanine, both in the free form, on the plasma and tissue concentrations of glutamine, glutamate, and glutathione (GSH) in rats subjected to long-duration exercise.MethodsRats were subjected to sessions of swim training. Twenty-one days before sacrifice, the animals were supplemented with DIP (1.5 g/kg, n = 6), a solution of free L-glutamine (1 g/kg) and free L-alanine (0.61 g/kg; GLN + ALA, n = 6), or water (CON, n = 6). Animals were sacrificed before (TR, n = 6) or after (LD, n = 6) long-duration exercise. Plasma concentrations of glutamine, glutamate, glucose, and ammonia and liver and muscle concentrations of glutamine, glutamate, and reduced and oxidized (GSSG) GSH were measured.ResultsHigher concentrations of plasma glutamine were found in the DIP-TR and GLN + ALA-TR groups. The CON-LD group showed hyperammonemia, whereas the DIP-LD and GLN + ALA-LD groups exhibited lower concentrations of ammonia. Higher concentrations of glutamine, glutamate, and GSH/GSSG in the soleus muscle and GSH and GSH/GSSG in the liver were observed in the DIP-TR and GLN + ALA-TR groups. The DIP-LD and GLN + ALA-LD groups exhibited higher concentrations of GSH and GSH/GSSG in the soleus muscle and liver compared with the CON-LD group.ConclusionChronic oral administration of DIP and free GLN + ALA before long-duration exercise represents an effective source of glutamine and glutamate, which may increase muscle and liver stores of GSH and improve the redox state of the cell.     

Effect of glutamine on gut glutathione fractional release in the implanted tumor model

Cancer and its treatments cause a marked depletion of glutamine (GLN). However, dietary GLN can restore this loss and improve the outcomes of the treatments. The reasons behind this need to be investigated. GLN is suggested to involve in glutathione (GSH) synthesis. Fast-growing tumors alter gut GLN metabolism, but the effect of tumor growth on gut GSH release remains unknown. We hypothesized that gut GSH release would decrease in the tumor-bearing host and this downregulation would be antagonized by supplemental GLN. Female Fisher-344 rats were randomized to the groups: GLN + TUMOR, Freamine (FA) + TUMOR, GLN + SHAM, and FA + SHAM. The rats were implanted with MTF-7 mammary tumors as tumor-bearing groups, whereas the rats were sham operated as control groups. The rats were pair fed chow, gavaged with 1 g/kg/day GLN or an isonitrogenous FA. Tumor growth, blood and gut mucosa GLN, glutamate, and/or GSH were measured. The gut extractions, defined as the difference of concentrations across the gut, were calculated. Supplemental GLN enhanced the gut GLN uptake and GSH release with tumor growth and significantly increased blood and gut mucosa GLN and/or GSH concentrations. Our results demonstrate the important antioxidant role of GLN and thus may have significant implications in nutritional immune modulation in cancer patients.     

Effect of glutamine supplementation on protein metabolism and glutathione in tumor-bearing rats

The effect of glutamine (GLN)-supplemented total parenteral nutrition (TPN) on tumor growth and protein metabolism was investigated in tumor-bearing rats. Six days after implantation of AH109A hepatoma, rats received isonitrogenous TPN without or with alanyl-glutamine (25% of total N) for a period of 6 days. Protein turnover was assessed by continuous infusion of l4C-leucine and levels of GLN and glutathione were determined in muscle, jejunum and liver. Diet had no effect on tumor parameters: weight (mean = 4.4 g), GLN and glutathione concentrations, protein synthesis rate and bromodeoxyuridine-labeling index. Body weight loss was less pronounced in the GLN group (-5.5 +/- 1.2 vs. -9.4 +/- 1.4 g/5d). Decrease in plasma and muscle GLN concentrations (-30% and -17% vs. healthy controls, respectively) was limited in tumor-bearing rats receiving GLN-enriched TPN (-15% and +3%). GLN-supplemented TPN increased muscle and jejunum fractional synthesis rates (36% and 25% vs. standard TPN, respectively) and reduced body protein breakdown in tumor-bearing animals (303 +/- 33 vs. 421 +/- 66 mumol Leu/Kg/h). Decrease in jejunum glutathione levels was partially abolished in the GLN group: -50% vs. -64% in the standard TPN group; no effect was noticed in other tissues. The authors conclude that GLN-supplemented TPN improves protein metabolism at both the whole body and the tissue level, and prevents GLN and glutathione deficiencies associated with tumor implantation.     

Postoperative glycyl-glutamine infusion reduces immunosuppression: partial prevention of the surgery induced decrease in HLA-DR expression on monocytes

BACKGROUND AND AIMS: Surgery, trauma and inflammation reduce HLA-DR expression on monocytes, which is associated with an increased susceptibility to infection and sepsis. Furthermore, surgery decreases plasma glutamine (GLN) levels. The expression of HLA-DR on human monocytes in vitro is dependent on the concentration of GLN in the culture medium. We therefore hypothesized that postoperative infusions of glutamine-dipeptides would prevent the decreased HLA-DR expression on monocytes. METHODS: Thirty patients undergoing major abdominal surgery were randomly allocated to receive either 1500 ml Vamin (control) or an isonitrogenic formulation containing Vamin and 500 ml glycyl-glutamine (35 g GLN; 0.5g/kg BW) (GLY-GLN), or Vamin and 500 ml alanyl-glutamine (35 g GLN; 0.5 g/kg BW) (ALA-GLN) as a continuous infusion over 48 h post-operatively. Immediately and 48 h after surgery blood samples were collected to determine HLA-DR expression on monocytes by flow cytometry. RESULTS: The groups were comparable with respect to age, gender distribution and operation time. In patients receiving GLY-GLN mean HLA-DR expression on monocytes at 48 h was significantly better preserved than in controls (65.0 %+/-7 % vs 42.5 %+/-4 %;P<0.05), whereas HLA-DR expression on monocytes in patients receiving ALA-GLN was not significantly different. CONCLUSION: This is the first study comparing the dipeptides GLY-GLN and ALA-GLN in the postoperative setting. The GLY-GLN induced preservation of HLA-DR on monocytes following surgery may prevent infectious complications in these patients.     

Effects of glutamine supplementation on innate immune response in rats with gut-derived sepsis

The present study examined the effect of glutamine (Gln)-enriched diets before sepsis or Gln-containing total parenteral nutrition (TPN) after sepsis, or both, on the phagocytic activity and blood lymphocyte subpopulation in rats with gut-derived sepsis. Rats were assigned to a control group or one of four experimental groups. The control group and groups 1 and 2 were fed a semipurified diet; groups 3 and 4 had part of casein replaced by Gln. After feeding the diets for 10 d, sepsis was induced by caecal ligation and puncture (CLP); TPN was maintained for 3 d after CLP. The control group and groups 1 and 3 were infused with conventional TPN and groups 2 and 4 were supplemented with Gln in the TPN solution. All rats were killed 3 d after CLP or sham operation to examine their immune responses. The results showed that compared with the control group, the phagocytic activities of peritoneal macrophages were enhanced in groups 3 and 4, but not in groups 1 and 2. The proportion of CD3+ cells in group 1 was significantly lower (P<0.05) than that of the control group, whereas no differences were observed among the control and Gln-supplemented groups. The CD4+ cell proportion was significantly lower (P<0.05) in group 1 compared with the control group and groups 3 and 4. These findings suggest that Gln-enriched diets before CLP significantly enhanced peritoneal macrophage phagocytic activity, preserved CD4+ cells and maintained blood total T lymphocytes in gut-derived sepsis. However, parenteral Gln administration after caecal ligation and puncture had no favourable effects on modulating immune response in septic rats.     

重组人生长激素和口服谷氨酰胺双肽联合应用改善严重烧伤患者内毒素血症的作用

目的探讨重组人生长激素(rhGH)和口服谷氨酰胺双肽(Glutaminedipeptide)改善严重烧伤病人内毒素血症的作用。方法36例烧伤总面积大于40%,Ⅲ度面积大于20%的患者加入研究,随机分为对照组(Controlgroup),谷氨酰胺双肽组(GLNgroup)和联合应用谷氨酰胺双肽及重组人生长激素组(GLN+rhGHgroup)。每组12人,对照组常规治疗;谷氨酰胺双肽组伤后1～14天口服谷氨酰胺双肽0.5g     

Glutamine supplementation enhances mucosal immunity in rats with Gut-Derived sepsis

OBJECTIVE: Supplemental glutamine (Gln) has been demonstrated to improve the immunologic response and reduce mortality in rodents with sepsis. However, the effects of Gln on gut-associated lymphoid tissue function after infection and sepsis are not clear. We investigated the effects of Gln-supplemented diets before sepsis, Gln-enriched total parenteral nutrition (TPN) after sepsis, or both on the intestinal immunity in rats with gut-derived sepsis. METHODS: Male Wistar rats were assigned to control and four experimental groups. The control and experimental groups 1 and 2 were fed a semi-purified diet; in experimental groups 3 and 4, part of the casein in the diets was replaced with Gln. After feeding rats the respective diets for 10 d, sepsis was induced by cecal ligation and puncture (CLP) in the experimental groups, whereas the control group underwent a sham operation; at the same time, the internal jugular vein of all rats was cannulated. All rats were maintained on TPN for 3 d. The control group and groups 1 and 3 were infused with conventional TPN, and groups 2 and 4 were given a TPN solution supplemented with Gln, which provided 25% of total amino acid nitrogen. All rats were killed 3 d after the sham operation or CLP. Intestinal immunoglobin A levels, total lymphocyte yields, and lymphocyte subpopulations in Peyer's patches were analyzed. RESULTS: Total Peyer's patch lymphocyte numbers were significantly higher in the Gln-supplemented groups than in the control group. Distributions of CD3+ and CD4+ in group 1 were significantly lower than those in the control group, whereas no differences were observed among the control and Gln-supplemented groups. Plasma immunoglobulin A levels were higher in the Gln-supplemented groups than the control group and group 1. Intestinal immunoglobulin A levels were significantly higher in groups 2 and 4 than in the control group and group 1. CONCLUSIONS: Preventive use of a Gln-supplemented enteral diet before CLP or intravenous Gln supplementation after CLP have similar effects in promoting proliferation of total lymphocyte in gut-associated lymphoid tissue, enhancing IgA secretion, and maintaining T-lymphocyte populations in Peyer's patches. Gln administered before and after CLP did not seem to have a synergistic effect on enhancing mucosal immunity in rats with gut-derived sepsis.     

Maintenance of skeletal muscle intracellular glutamine during standard surgical trauma

Skeletal muscle glutamine (GLN) concentration falls following injury and infection. In an attempt to prevent this decline and to characterize its influence on the efflux of amino acid (AA) from skeletal muscle, we administered varying quantities of AA (0,2, and 4 g/kg X day) as saline or AA solutions with or without GLN enrichment to 22 postoperative dogs. Plasma and muscle AA were determined before and 24 hr after standard laparotomy. Hindquarter AA efflux was measured at 6 and 24 hr. Skeletal muscle nitrogen declined in saline controls (69.8 +/- 8.5 vs 52.8 +/- 8.4 mmol/liter; p less than 0.01), largely due to the fall in intracellular GLN (21.48 +/- 3.21 vs 15.86 +/- 3.80; p less than 0.05). Similar alterations were seen in the animals receiving 2 g/kg. However, both intracellular nitrogen and GLN were maintained in animals receiving 4 g/kg, whether the AA solutions contained GLN or not (skeletal muscle nitrogen before 64.3 +/- 8.6 mmol/l vs 65.4 +/- 7.0 after, GLN 19.2 +/- 3.4 vs 19.9 +/- 3.0). Hindquarter AA efflux was reduced in those animals at 6 hr compared with saline-treated animals (-6.52 +/- 1.8 and -7.70 +/- 5.90 vs -19.05 +/- 4.06 mumol/kg X min; p less than 0.05). Intracellular GLN can be maintained during operative stress with adequate nitrogen infusion. Replacing 50% of the balanced AA solution with GLN resulted in equally effective maintenance of intracellular GLN levels and a comparable reduction in skeletal muscle AA efflux. Preservation of normal intracellular GLN levels with adequate AA nutrition may be essential for the conservation of muscle protein.     

Effect of glutamine on the initiation and promotion phases of DMBA-induced mammary tumor development

BACKGROUND: Oral glutamine (GLN) has been shown to up-regulate tissue glutathione (GSH), augment natural killer (NK) cell activity, and prevent tumor growth in an implantable breast cancer model (MTF-7). We hypothesized that dietary GLN would likewise antagonize the induction or promotion of tumor formation by 7,12-dimethylbenz[a]anthracene (DMBA) via up-regulation of GSH or augmentation of NK activity. METHODS: At age 55 days, 81 Sprague-Dawley rats were gavaged with a one-time dose of 80 mg/kg DMBA, time 0. Rats were randomized into 3 groups (GLN+DMBA, Freamine [FA]+DMBA, water (H2O)+DMBA), pair-fed chow, and gavaged with 1.0 g/kg/day GLN or isonitrogenous amount of FA or H2O for the indicated times: PreFed (-1 to + 16 weeks), Short-Fed (-1 to + 1 weeks) and PostFed (+ 1 to +16 weeks). After 16 weeks, rats were killed and examined for mammary tumors, blood was assayed for GLN and GSH content, and spleens were assayed for NK cytotoxicity. RESULTS: Over the 4-month study period, there was no significant difference in tumorigenesis between FA and H2O groups, regardless of timing of feeding and amino acid diet, except GLN. In Pre- and PostFed GLN groups, there was no significant difference between groups, but there were significant decreases in tumorigenesis in GLN groups compared with either FA or H2O groups. However, in the Short-Fed group, there was no significant difference in tumorigenesis from the GLN, FA, or H2O groups. CONCLUSIONS: Continuously supplemented GLN significantly reduced DMBA-induced breast cancer growth when compared with the non-GLN-supplemented and Short-Fed supplemental GLN groups. Furthermore, GLN appears to have its primary effect on promotion and not initiation of tumor formation. This decreased tumor formation was associated with significantly higher arterial GLN and GSH levels and NK activity at killing in the GLN+DMBA group. Protein in the presentation of FA did not promote or prevent tumor growth. These data indicate that GLN may be useful in the chemoprevention of breast cancer.     

Enteral nutrition supplemented with L-glutamine in patients with systemic inflammatory response syndrome due to pulmonary infection

ObjectiveTo evaluate the effect of enteral nutrition (EN) supplemented with l-glutamine on glycolytic parameters, inflammation, immune function, and oxidative stress in moderately ill intensive care patients with sepsis.MethodsThirty patients received EN. Fifteen patients received EN supplemented with glutamine (30 g; GLN group) for 2 d followed by EN supplemented with calcium caseinate (30 g, CAS group), also over 2 d. The other 15 patients received EN with calcium caseinate (30 g; CAS group) for 2 d followed by EN with glutamine (30 g; GLN group), also over 2 days. One washout day with only EN was provided between every 2-d period of EN plus supplementation to all patients. Blood samples were taken before and after supplementation.ResultsThere were no changes in glycolytic parameters in either group. Leukocytes decreased in the two groups (from 13 650 to 11 500 in the CAS group, P = 0.019; from 12.850 to 11.000 in the GLN group, P = 0.046). Lymphocytes increased in the GLN group (from 954 to 1916, P < 0.0001) and were more numerous after glutamine supplementation (from 1916 to 1085, P < 0.0001, GLN versus CAS). No significant changes were observed in interleukin levels, but urea levels were higher in the GLN compared with the CAS group (50.0–47.0, P = 0.030). Glutathione plasma concentrations did not differ significantly between the groups. No significant changes were observed in the plasma glutamine and glutamate concentrations.ConclusionsThe EN supplemented with glutamine increased the lymphocyte count and helped to decrease lipid peroxidation but presented no effect on the antioxidant glutathione capacity and on cytokine concentrations or glycolytic parameters.     

Oral free and dipeptide forms of glutamine supplementation attenuate oxidative stress and inflammation induced by endotoxemia

ObjectiveThe aim of the present study was to determine the effects of oral supplementation with l-glutamine plus l-alanine (GLN+ALA), both in the free form and l-alanyl-l-glutamine dipeptide (DIP) in endotoxemic mice.MethodsB6.₁₂₉ F₂/J mice were subjected to endotoxemia (Escherichia coli lipopolysaccharide [LPS], 5 mg/kg, LPS group) and orally supplemented for 48 h with either l-glutamine (1 g/kg) plus l-alanine (0.61 g/kg) (GLN+ALA-LPS group) or 1.49 g/kg DIP (DIP-LPS group). Plasma glutamine, cytokines, and lymphocyte proliferation were measured. Liver and skeletal muscle glutamine, glutathione (GSH), oxidized GSH (GSSG), tissue lipoperoxidation (TBARS), and nuclear factor (NF)-κB–interleukin-1 receptor-associated kinase 1 (IRAK1)–Myeloid differentiation primary response gene 88 pathway also were determined.ResultsEndotoxemia depleted plasma (by 71%), muscle (by 44%), and liver (by 49%) glutamine concentrations (relative to the control group), which were restored in both GLN+ALA-LPS and DIP-LPS groups (P < 0.05). Supplemented groups reestablished GSH content, intracellular redox status (GSSG/GSH ratio), and TBARS concentration in muscle and liver (P < 0.05). T- and B-lymphocyte proliferation increased in supplemented groups compared with controls and LPS group (P < 0.05). Tumor necrosis factor-α, interleukin (IL)-6, IL-1 β, and IL-10 increased in LPS group but were attenuated by the supplements (P < 0.05). Endotoxemic mice exhibited higher muscle gene expression of components of the NF-κB pathway, with the phosphorylation of IκB kinase-α/β. These returned to basal levels (relative to the control group) in both GLN+ALA-LPS and DIP-LPS groups (P < 0.05). Higher mRNA of IRAK1 and MyD88 were observed in muscle of LPS group compared with the control and supplemented groups (P < 0.05).ConclusionOral supplementations with GLN+ALA or DIP are effective in attenuating oxidative stress and the proinflammatory responses induced by endotoxemia in mice.     

谷氨酰胺对大鼠烧伤后代谢率变化及相关激素分泌的影响

目的　探讨谷氨酰胺对大鼠烧伤后代谢率变化及相关激素分泌的影响。方法　采用 3 0 %体表面积Ⅲ度烧伤大鼠模型 ,将 88只Wistar大鼠随机分为烧伤对照 (B)组和谷氨酰胺 (GLN)组。两组大鼠采用等氮、等热卡的营养支持 ,GLN组予 1 0g/kg dGLN ,B组予等量的甘氨酸。观察了伤前及伤后 (PBD) 1、3、5、7、10d大鼠静息能量代谢率 (REE)的变化 ,检测了血中胰岛素、胰高血糖素及皮质醇的含量 ,并进行相关分析。结果　烧伤后两组大鼠的REE、血浆胰岛素、胰高血糖素和皮质醇含量均明显高于伤前。两组相比 ,GLN组的REE明显低于B组 ,血浆胰高血糖素和皮质醇略低于B组 ,胰岛素含量略高于B组 ,在PBD3～ 5存在显著差异。而胰岛素及胰岛素 /胰高血糖比值则明显高于B组 ,在PBD1～ 10存在显著差异 ( P <0 0 5 ,P <0 0 1)。相关分析显示 ,REE同胰岛素 /胰高血糖素比值呈显著负相关 (r=-0 78,P <0 0 5 )。结论　烧伤大鼠代谢率明显增高 ,服用谷氨酰胺能有效降低烧伤后高代谢反应 ,其机制与谷氨酰胺能促进合成激素分泌 ,降低分解激素释放有关     

Glutamine therapy improves outcome of in vitro and in vivo experimental colitis models

Background: Pharmacologic doses of glutamine (GLN) can improve clinical outcome following acute illness and injury. Recent studies indicate enhanced heat shock protein (HSP) expression is a key mechanism underlying GLN's protection. However, such a link has not yet been tested in chronic inflammatory states, such as experimental inflammatory bowel disease (IBD). Methods: Experimental colitis was induced in Sprague‐Dawley rats via oral 5% dextran sulfate sodium (DSS) for 7 days. GLN (0.75 g/kg/d) or sham was administered to rats by oral gavage during 7‐day DSS treatment. In vitro inflammatory injury was studied using YAMC colonic epithelial cells treated with varying concentrations of GLN and cytokines (tumor necrosis factor–α/interferon‐γ). Results: Pharmacologic dose, bolus GLN attenuated DSS‐induced colitis in vivo with decreased area under curve for bleeding (8.06 ± 0.87 vs 10.38 ± 0.79, P < .05) and diarrhea (6.97 ± 0.46 vs 8.53 ± 0.39, P < .05). This was associated with enhanced HSP25 and HSP70 in colonic mucosa. In vitro, GLN enhanced cell survival and reduced proapoptotic caspase3 and poly(ADP‐ribose) polymerase cleavage postcytokine injury. Cytokine‐induced inducible nitric oxide synthase expression and nuclear translocation of nuclear factor‐κB p65 subunit were markedly attenuated at GLN concentrations above 0.5 mmol/L. GLN increased cellular HSP25 and HSP70 in a dose‐dependent manner. Conclusions: These data demonstrate the therapeutic potential of GLN as a “pharmacologically acting nutrient” in the setting of experimental IBD. GLN sufficiency is crucial for the colonic epithelium to mount a cell‐protective, antiapoptotic, and anti‐inflammatory response against inflammatory injury. The enhanced HSP expression observed following GLN treatment may be responsible for this protective effect.     

Oral glutamine and the healing of colonic anastomoses in rats

BACKGROUND: Recent evidence has suggested that glutamine is one of the primary energy sources of the colon. The aim of this study was to evaluate the effects of oral glutamine supplementation on the healing of colonic anastomoses in rats. METHODS: Forty-eight adult male Wistar rats, weighing 174.41 +/- 37.39 g, were housed in individual cages. All rats had free access to water and standard rat chow. The rats were randomized to receive daily, for 7 days before the operation and during the postoperative period, 10% L-glutamine (GLN group) or 10% glycine (GLY group) in isonitrogenous and isovolumetric solutions (1.5 g/kg per day), through an orogastric tube. On the eighth day, rats were anesthetized and subjected to 2 colonic transections, one 6 cm distal from the ileocecal valve and another 5 cm distal from the first transection. Bowel continuity was restored by 2 end-to-end, single layer, everted, anastomoses with 8 interrupted sutures (6-0 nylon). After the operation, the rats were kept in individual cages and had free access to water and rat chow. One-half of the rats in each group were killed either on postoperative day 3 or 8, and the 2 colonic anastomoses of each animal were resected and stored in 0.9% saline and 10% formalin for tensile strength and histologic (hematoxylineosin and collagen densitometry) studies, respectively. Student's t-test and Kruskal Wallis tests were used for statistical analysis. RESULTS: Total rupture strength was significantly higher in the GLN group (GLN: 0.068 +/- 0.045 kgf versus GLY: 0.042 +/- 0.027 kgf, p = .04). The mean monocytes infiltrate was significantly smaller in the GLN group (p = .04). The collagen densitometry analysis demonstrated greater percent area of type I (mature) in the GLN group compared with GLY (58.65 +/- 11.70% versus 41.79 +/- 10.54%, p = .0000), respectively. Subgroup analyses according to the day of rat death were still significant: GLN 3: 54.22 +/- 10.02% versus GLY 3: 41.92 +/- 13.31% (p = .04) and GLN 8: 62.63 +/- 12.13% versus GLY 8: 41.67 +/- 7.69% (p = .0004). Type III collagen (immature) percent area was significantly smaller in the GLN group's colonic anastomoses (GLN: p = .0000; GLN 3: p = .04 and GLN 8: p = .0003, respectively). CONCLUSIONS: Perioperative oral glutamine supplementation increases total rupture strength and improves the percent area of mature collagen at the anastomoses sites on postoperative days 3 and 8.     

Glutamine Supplementation Decreases Intestinal Permeability and Preserves Gut Mucosa Integrity in an Experimental Mouse Model

Background: Glutamine (GLN) is the preferred fuel for enterocytes, and GLN supplementation is critical during stressful conditions. The aim of this study was to evaluate the effect of GLN on intestinal barrier permeability and bacterial translocation in a murine experimental model. Methods: Swiss male mice (25–30 g) were randomized into 3 groups: (1) sham group; (2) intestinal obstruction (IO) group; (3) IO and GLN (500 mg/kg/d) group. Two different experiments were carried out to assess intestinal permeability and bacterial translocation. In the first experiment, the animals were divided into the 3 groups described above and received diethylenetriamine pentaacetate radiolabeled with technetium (^99mTc) on the eighth day. At different time points after intestinal obstruction, blood was collected to determine radioactivity. The animals were killed, and the small intestine was removed for histological analyses. In the bacterial translocation study, on the eighth day all groups received Escherichia coli labeled with ^99mTc. After 90 minutes, the animals underwent intestinal obstruction and were killed 18 hours later. Blood, mesenteric lymph nodes, liver, spleen, and lungs were removed to determine radioactivity. Statistical significance was considered when P ≤ .05. Results: The levels of intestinal permeability and bacterial translocation were higher in the IO group than in the sham and GLN groups (P < .05). GLN decreased intestinal permeability and bacterial translocation to physiologic levels in the treated animals and preserved intestinal barrier integrity. Conclusions: GLN had a positive impact on the intestinal barrier by reducing permeability and bacterial translocation to physiologic levels and preserving mucosal integrity.