Glutamine relieves the hypermetabolic response and reduces organ damage in severe burn patients: A multicenter, randomized controlled clinical trial.

BACKGROUND: Severe burns can cause a hypermetabolic response and organ damage. Glutamine is a conditionally essential amino acid with various pharmacological effects. In this study, whether glutamine could alleviate the hypermetabolic response and maintain organ function after burn injury was analyzed. METHODS: A multicenter, randomized, single-blind, parallel controlled trial was conducted to evaluate the efficacy of glutamine in decreasing hypermetabolism after burn injury. Physiological and biochemical indexes, such as vital signs, metabolic hormones, metabolic rate, and organ damage, were recorded on the 7th and 14th days after treatment. RESULTS: In total, 55 adult burn patients with a total burn surface area (TBSA) of 30-70% were included in this study and randomly divided into the burn control (B, 28 patients) and burn+glutamine (B+G, 27 patients) groups. Except for the glutamine administration, the groups did not differ in the other treatments and nutrition supplements. The levels of diamine oxidase (DAO), lactulose/mannitol (L/M), ß2-microglobulin, lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBD) and cardiac troponin l (cTnl) in the B+G group were significantly lower than those in the B group (p < 0.05 or 0.01). The levels of resting energy expenditure (REE), serum catecholamines, glucagon, lactate and Homeostasis model assessment (HOMA) in the B+G group were significantly lower than those in the B group (p < 0.05 or 0.01). No significant difference was found in the length of hospitalization or the mortality rate between the two groups (p > 0.05). CONCLUSIONS: Glutamine moderately alleviates the hypermetabolic response and reduces organ damage after severe burns. Therefore, the early application of glutamine, which is effective and safe, should be used as an active intervention as early as possible.

Effects of intestinal trefoil factor on intestinal mucus barrier in burned mice.

Severe burns might cause intense inflammatory response and tissue ischemia and hypoxia, and these effects result in intestinal mucosal barrier damage. In this study, we evaluated the effects of recombinant human intestinal trefoil factor (rhITF) on the intestinal mucus barrier after burn injury. The results showed that rhITF could improve the intestinal mucosal damage index, decrease diamine oxidase (DAO) activity, reduce intestinal damage, and thereby alleviate intestinal mucous permeability. Severe burns were associated with subsequent decreases in the mucus thickness and the levels of hexose, and mucin, and rhITF administration might partially reverse these changes. Additional experiments showed that supplementation with rhITF markedly increased the mitochondrial respiratory control rate (RCR) and phosphorus-oxygen ratio (P/O) in intestinal tissue. Moreover, rhITF improved the intestinal mucosal blood flow (IMBF) and the levels of oxygen extraction (Oext), nitric oxide (NO) and ATP. These results suggest that ITF can improve the blood perfusion of the intestinal mucosa after severe burns, promote the transport of glutamine in the intestinal mucosa, improve the energy metabolism of goblet cells, stimulate goblet cell differentiation and maturation, promote the synthesis and secretion of intestinal mucus, and maintain the barrier function of intestinal mucus.

Effectiveness and mechanism study of glutamine on alleviating hypermetabolism in burned rats.

OBJECTIVES: This study aimed to explore the effects of glutamine on hypermetabolic reactions in burned rats and its underlying mechanism. METHODS: Fifty-five Sprague-Dawley rats were randomly divided into three groups, namely, the control (C), burned (B), and burned + glutamine (B + G) groups. Rats in the glutamine treatment group were supplemented with 1 g glutamine per kg body weight. Changes in body weight and resting energy expenditure in all groups were observed daily. Blood glucose and glucose tolerance level were measured on days 1, 3, 7, 10 and 14 after burn injury. On days 7 and 14 after injury, the rats were sacrificed, and the weight and protein content of the skeletal muscle were measured. Moreover, the level of glutamine, inflammatory mediator, nicotinamide adenine dinucleotide phosphate (NADPH), glutathione, and the activity of glutamine metabolic enzymes were measured. RESULTS: The hypermetabolic reaction after burn injury was significantly inhibited by glutamine administration, and the range of variations in the resting energy expenditure and body weight indicators was narrowed remarkably (P < 0.05 or 0.01), whereas the weight and protein content of the skeletal muscle returned to normal (P < 0.05 or 0.01). Glutamine could increase glutaminase activity in various tissues, promote the utilization of glutamine, and appropriately reduce the degree of organ damage and inflammatory response (P < 0.05 or 0.01). Furthermore, glutamine could promote the synthesis of the reducing substances NADPH and glutathione (P < 0.05 or 0.01). CONCLUSIONS: Glutamine administration effectively reduces hypermetabolic reactions by promoting NADPH synthesis, inhibiting oxidative stress, and improving glutamine utilization after burn injury.

Mechanistic study of PDIA1-catalyzed TFF3 dimerization during sepsis.

AIMS: Trefoil factor 3 (TFF3) is a gut mucosal protective molecule that is secreted by intestinal goblet cells. The dimeric structure of TFF3 enables it to function in intestinal mucosal repair and to maintain its own stability. Protein disulfide isomerase a1 (PDIA1) can directly catalyze the formation, isomerization and reduction of disulfide bonds in proteins and may play an important role in the formation of TFF3 dimer. In this study, we focused on the specific molecular mechanism of TFF3 dimerization by PDIA1 and the changes during sepsis. METHODS: We examined the changes of PDIA1 and TFF3 in sepsis rats and cell models and used a variety of experimental techniques to investigate the specific molecular mechanism of PDIA1-catalyzed TFF3 dimerization. KEY FINDINGS: We found that PDIA1 can directly catalyze the dimerization of TFF3. Our MD model proposed that two TFF3 monomers form hydrogen bonds with the region b' of PDIA1 through two stepwise reactions. Furthermore, we propose that the Cys24-Cys27 active site at the region a' of PDIA1 mediates disulfide bond formation between the Cys79 residues of each of the two TFF3 monomers via deprotonation and nucleophilic attack. During sepsis, PDIA1 is downregulated and the excessive release of nitric oxide (NO) promoted PDIA1 nitrosylation. This modification reduced PDIA1 activity, which resulted in the corresponding decrease of TFF3 dimerization and compromised TFF3 dimer function. SIGNIFICANCE: Our study revealed a novel mechanism for the inhibition of intestinal mucosal repair during sepsis and revealed novel targets for the prevention and treatment of sepsis.

Effects of glutamine on intestinal mucus barrier after burn injury.

Severe burns may cause intense stress and persistent inflammation, resulting in intestinal mucosal barrier damage. In this study, we evaluated the effects of glutamine (Gln) on intestinal mucus barrier after burn injury. The results showed that glutamine could improve intestinal mucosal blood flow (IMBF), decrease diamine oxidase (DAO) activity, and reduce intestine damage, thereby alleviate intestinal mucous permeability. Severe burn was associated with subsequent decrease in mucus thickness, levels of hexose, sialic acid, and protein. Glutamine administration might partially reverse these changes. Additional experiments showed that supplementation with glutamine could markedly raise the content of glutamine, glutathione (GSH), and ATP in intestinal tissue. Moreover, the levels of mRNA and protein expression of MUC2, intestinal trefoil factor (ITF) were increased remarkably, but contrary to the trend of GRP-78, CHOP. These results suggest that glutamine can improve tissue perfusion and increase energy synthesis in enterocytes, decrease endoplasmic reticulum stress (ERS) and improve mucin and ITF synthesis. Finally, lessen intestinal mucus barrier damage after burn injury.

Glutamine protects intestinal mucosa and promotes its transport after burn injury in rats.

Glutamine is an important energy source for intestinal epithelial cells (IEC); however, it is still controversial whether glutaminecan be fully utilized under pathological conditions. In this study, we investigated the changes in glutamine transport after burns and assessed the effects of exogenous glutamine administration. Finally, the potential underlying mechanisms were explored. Experimental rats were randomly divided into three groups: control group (C); burn group (B); burn+glutamine group (B+G). Rats in groups B+G and B received intragastric administration of isodose glutamine or alanine, respectively. At days 1, 3 and 5 after burns, the structure of intestinal mucosa and brush-border membrane vesicles (BBMV) were observed. The glutamine transport capacity of IEC and BBMV was detected. The synthesis of glutamine transporter ASCT2 and B0AT1 was determined. Moreover, the intestinal mucosal blood flow (IMBF), diamine oxidase activity, and the glutamine and ATP content were measured. The results showed that burn injury caused structural damage to IECs and BBMV, and significantly impaired the ability for glutamine transportation. Moreover, the mRNA and protein expressions of ASCT2 and B0AT1 as well as the glutamine and ATP content were markedly decreased. Compared with group B, most of these indicators in group B+G showed significant improvement, and approached normal levels. We conclude that glutamine administration can relieve intestinal damage, improve IMBF, promote energy synthesis and alleviate endoplasmic reticulum stress after burn injury. Finally, the synthesis and modification of ASCT2 and B0AT1 are promoted, which ultimately enhances intestinal glutamine transport.

The application of early goal directed therapy in patients during burn shock stage.

Early goal directed therapy (EGDT) provided at the earliest stages of burn shock, has significant benefits for ordinary burn patients, however, its effect on patients with more than 80% of total surface area burned (TBSA) still remains unclear. In this study, 34 extensively burned patients with (87.3±5.6)% of total surface area burned were collected from January 2008 to January 2014. All burn patients here had similar monitoring or treatment modalities. Of these 34 burn patients, 13 patients were treated with EGDT under pulse indicator continuous cardiac output (PICCO) monitoring, and 21 patients were treated with conventional fluid management. Information obtained in the course of treatment included mean arterial pressure (MAP), central venous oxygen saturation (ScvO2), oxygenation index (PaO2/FiO2), blood lactic acid and urine volume, infusion volume (mL·1% TBSA-1·Kg-1), complications of over-resuscitation (hydrothorax or pulmonary edema), case rate of burn sepsis and fatality. Our results demonstrated that there existed significant difference between the two groups in parameters below: 1. Higher ScvO2 (%) after EGDT (EGDT: 78.1±8.6, CG: 65.5±11.2; t=-3.446, P<0.05), 2. Higher PaO2/FiO2 after EGDT (EGDT: 381.4±56.6, CG: 328.9±48.6; t=2-875, P<0.05), 3. Lower mean infusion volume after EGDT (mL·1% TBSA-1·Kg-1) (EGDT: 3.29±0.26, CG: 3.71±0.31; t=5.292, P<0.05), 4. Lower complications of over-resuscitation after EGDT (EGDT: 2/13, CG: 15/21; P<0.05); However, no statistical significance existed in parameters below: 1. MAP (EGDT: 76.2±13.1, CG: 74.3±15.6; t=-0.36, P>0.05), 2. Urine volume (EGDT: 0.83±0.12, CG: 0.85±0.17; t=0.370, P>0.05), 3. Case of burn sepsis (EGDT: 13/13, CG: 20/21; P=1), 4. Case fatality (EGDT: 1/13, CG: 3/21; P=1). The finding results showed that patients with more than 80% of total surface area burned during burn shock phase could get better outcome from EGDT.