Standard Total Parenteral Nutrition Research Articles

Effect of glutamine or glucagon-insulin enriched total parenteral nutrition on liver and gut in 70% hepatectomized rats with colon stenosis

Background: Malnutrition of enterocytes is believed to facilitate the breakdown of the intestinal mucosal barrier, furthering a translocation of enteric bacteria with subsequent severe infection, which has been described after extensive hepatectomy. Glutamine and glucagon insulin are said to attenuate the malnutrition of enterocytes. To determine whether this was true, the effects on the remnant liver and the gut of total parenteral nutrition supplemented by admixtures of glutamine and/or glucagon insulin were investigated in rats subjected to massive hepatectomy and transient intestinal stasis. Study Design: Rats underwent a permanent cannulation of the superior caval vein without restraining their mobility, a 70% hepatectomy, and a 24 hour string-ligation stenosis of the colon. A standard total parenteral nutrition solution was infused without or with 2% glutamine and without or with glucagon-insulin supplementation, respectively. Results: Glutamine and glucagon-insulin supplemented total parenteral nutrition increased ileal mucosal DNA concentrations during and after intestinal stasis. Glutamine or glucagon-insulin alone had less pronounced effects. In the liver, the combined supplementation resulted in reduced adenosine triphosphate concentrations and increased mitochondrial adenosine triphosphate synthesis as well as in an early increase in DNA concentrations. Conclusion: Glutamine and glucagon-insulin enriched total parenteral nutrition attenuates malnutrition of enterocytes after massive abdominal stress and promotes liver regeneration after extensive hepatectomy.

Effect of glutamine or glucagon-insulin enriched total parenteral nutrition on liver and gut in 70% hepatectomized rats with colon stenosis.

Malnutrition of enterocytes is believed to facilitate the breakdown of the intestinal mucosal barrier, furthering a translocation of enteric bacteria with subsequent severe infection, which has been described after extensive hepatectomy. Glutamine and glucagon insulin are said to attenuate the malnutrition of enterocytes. To determine whether this was true, the effects on the remnant liver and the gut of total parenteral nutrition supplemented by admixtures of glutamine and/or glucagon insulin were investigated in rats subjected to massive hepatectomy and transient intestinal stasis. Rats underwent a permanent cannulation of the superior caval vein without restraining their mobility, a 70% hepatectomy, and a 24 hour string-ligation stenosis of the colon. A standard total parenteral nutrition solution was infused without or with 2% glutamine and without or with glucagon-insulin supplementation, respectively. Glutamine and glucagon-insulin supplemented total parenteral nutrition increased ileal mucosal DNA concentrations during and after intestinal stasis. Glutamine or glucagon-insulin alone had less pronounced effects. In the liver, the combined supplementation resulted in reduced adenosine triphosphate concentrations and increased mitochondrial adenosine triphosphate synthesis as well as in an early increase in DNA concentrations. Glutamine and glucagon-insulin enriched total parenteral nutrition attenuates malnutrition of enterocytes after massive abdominal stress and promotes liver regeneration after extensive hepatectomy.

Effect of methionine-free total parenteral nutrition and insulin-like growth factor I on tumor growth in rats.

The objectives of this study were to evaluate the effect of insulin-like growth factor I (IGF-I) on the fractional synthesis rate (FSR) of muscle and whole body protein breakdown rate (WPBR) during methionine-free total parenteral nutrition (MTPN). We also determined whether the inhibition of endogenous methionine availability reduced tumor protein synthesis. AH109A hepatoma cells were inoculated onto the backs of Donryu rats on day 0. On day 10, the rats were catheterized for TPN and assigned to one of four groups: 1) standard TPN (STPN), 2) STPN + IGF-I, 3) MTPN, or 4) MTPN + IGF-I. The addition of IGF-I to MTPN reduced the loss of body weight by both increasing muscle FSR and reducing WPBR. The tumor FSR did not differ between MTPN + IGF-I and MTPN. The methionine extraction ratio from the liver was negative with MTPN + IGF-I but positive in the other groups. We concluded that IGF-I blockage of endogenous methionine release from peripheral protein sites was associated with a shift to liver-derived methionine, with no change in tumor growth in MTPN-treated rats.

Contrasting effects of identical nutrients given parenterally or enterally after 70% hepatectomy: Bacterial translocation

High mortality occurs in rats with 70% hepatectomy fed intravenous (IV) total parenteral nutrition (TPN; 13.9% glucose, 4.17% amino acids, 1.46% fat, electrolytes, trace minerals, and vitamins providing 216 kcal·kg −1·d −1) but not when the identical nutrients are given at the same rate enterally (gastrostomy). We hypothesized that a difference in bacterial translocation (BT) was a contributing factor to this phenomenon. Forty-five male Sprague-Dawley rats (300–360 g) were divided into five groups and underwent the following: control (no operation), sham (intraperitoneal [IP] pentobarbital anesthesia, central venous and gastrostomy catheters, laparotomy, sham hepatectomy), standard oral feeding (SOF), TPN (IV nutrients), and total enteral nutrition (TEN; gastrostomy). The SOF, TPN, and TEN groups had IP pentobarbital anesthesia, central venous and gastrostomy catheters, and 70% hepatectomy. Postoperatively, control and SOF (both catheters plugged) rats ate a commercial rat chow and drank tap water ad libitum pre- and postoperatively. The sham, TPN, and TEN groups were given the identical infusate composition as above, but the nutrient concentrations were cut in half (110 kcal/kg) and three-quarters (165 kcal/kg) on postoperative days 1 and 2, respectively. At the end of postoperative day 2, all rats were euthanized. BT to mesenteric lymph nodes (MLNs), liver, spleen, and lungs was significantly higher in the TPN rats compared with all other groups, except that BT to the MLNs was similar in the TPN and TEN groups. Bacteremia was found only in the TPN rats. BT in TPN rats with 70% hepatectomy was significantly greater 48 h after operation than in those fed the identical nutrients enterally at the same rate; this correlates with the previously reported significantly greater mortality in rats with 70% hepatectomy receiving TPN.

Glutamine and arginine metabolism in tumor-bearing rats receiving total parenteral nutrition

Arginine supplementation increases glutamine levels in muscle and plasma. Since glutamine production is increased in catabolic states, these observations prompted us to investigate whether the flux of arginine to glutamine was increased in tumor-bearing (TB) rats, and we measured the synthesis rate of glutamine from arginine in control versus TB rats receiving standard total parenteral nutrition (TPN) solution. Male Donryu rats (N = 36; body weight, 200 to 225 g) were divided into two groups, control and TB rats. Yoshida sarcoma cells (1 × 10 6) were inoculated into the back of the rats (n = 18) subcutaneously on day 0. The rats were given free access to water and rat chow. On day 5, all animals, including non-TB rats (n = 18), were catheterized at the jugular vein and TPN was begun. On day 10, TPN solution containing either U- 14C-glutamine (2.0 μCi/h) or U- 14C-arginine (2.0 μCi/h) was infused as a 6-hour constant infusion. At the end of the isotope infusion, plasma was collected to determine the glutamine production rate in rats receiving U- 14C-glutamine, and the ratio of specific activity of glutamine to specific activity of arginine was measured in rats receiving U- 14C-arginine. Only 2 g tumor caused a decrease in glutamine levels and an increase in glutamine and arginine production. The low flux rate of arginine to glutamine was observed in control rats (Arg to Gln, 41.0 ± 11.9 μmol/kg/h). On the other hand, TB caused a significant increase in Arg to Gln compared with the control (213.3 ± 66.1 μmol/kg/h, P < .01 v control). An increase in the flux rate of Arg to Gln was associated with an enhancement in the ratio of specific activity of ornithine to specific activity of arginine in TB rats (control 51.5% ± 10.9% v 77.4% ± 8.9%, P < .05). We conclude that (1) glutamine and arginine metabolism is altered with very small tumors, (2) although the flux of Arg to Gln was increased in TB and rats, the small increase in Arg to Gln cannot explain the observed large increase in Gln production.

Short-chain fatty acid-supplemented total parenteral nutrition enhances functional adaptation to intestinal resection in rats

BACKGROUND & AIMS: Intestinal adaptation is a complex physiological process that is not completely understood. Total parenteral nutrition (TPN) induces intestinal atrophy that is prevented by the systemic administration of short-chain fatty acids (SCFAs) as measured by morphological indices (i.e., mucosal weight and mucosal DNA, RNA, and protein concentration). The aim of this study was to examine the effect of SCFA-supplemented TPN on functional markers of intestinal adaptation.METHODS: Forty-eight male Sprague-Dawley rats underwent an 80% jejunoileal resection and jugular catheterization. Rats received standard TPN or an isoenergetic, isonitrogenous TPN supplemented with SCFA (TPN + SCFA). Animals were further randomized to receive nutrient solutions for 3 or 7 days.RESULTS: Ileal uptakes of D-glucose were higher (P < 0.05) in both TPN + SCFA groups. Expression of glucose transporter (GLUT)2 messenger RNA (mRNA) was higher (P < 0.007) in the TPN + SCFA group at day 3. Expression of sodium-dependent glucose transporter 1 tended to be higher in both TPN + SCFA groups (P = 0.1). Na+,K+-adenosine triphosphatase mRNA was significantly more abundant in the TPN groups. GLUT5 and sucrase-isomaltase mRNA abundance did not differ between groups.CONCLUSIONS: Intravenous SCFAs facilitate intestinal adaptation after resection by increasing basolateral intestinal nutrient transport. The addition of SCFAs to current TPN formulations may be warranted to improve functional characteristics of the gastrointestinal tract.(Gastroenterology 1997 Mar;112(3):792-802)

Alanyl-glutamine-supplemented total parenteral nutrition improves survival and protein metabolism in rat protracted bacterial peritonitis model.

The effects of glutamine-enriched total parenteral nutrition (TPN) solution on survival, and protein turnover in the whole body and in individual organs were investigated in a rat protracted peritonitis model. Twenty-three rats underwent venous catheter insertion. Osmotic pumps were implanted in the peritoneal cavity to allow continuous delivery of Escherichia coli (4 x 10(8) CFU/d). The conventional TPN group received a conventional amino acid solution. The Ala-Gln TPN group received an alanyl-glutamine-enriched TPN solution. The two TPN solutions were isocaloric and isonitrogenous. Over the 5 days of TPN treatment, the survival rate of the Ala-Gln group was significantly higher than that of the conventional group. The Ala-Gln group tended to have increased whole-body protein turnover compared with the conventional group. Fractional protein synthetic rates (FSR) in the liver and gastrocnemius muscle of the Ala-Gln group were significantly higher than those of the conventional group. The serum glutamine concentration correlated positively with the FSR of both liver and muscle. The Ala-Gln group showed significantly greater mucosal height and mitoses per crypt, in the small intestine, than did the conventional group. Our results suggested that, in comparison with standard glutamine-free TPN, Ala-Gln-supplemented TPN increases protein synthesis in the liver and skeletal muscle, protects the morphology of the intestinal mucosa, and improves survival in protracted bacterial peritonitis. Ala-Gln supplementation may be useful in septic patients.

Effect of glutamine supplementation on protein metabolism and glutathione in tumor-bearing rats: S. Yoshida, A. Kaibara, K. Yamasaki, N. Ishibashi, T. Noake, T. Kakegawa JPEN 1995; 19: 492–497

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 μmol 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.

Short-chain fatty acid-supplemented total parenteral nutrition improves nonspecific immunity after intestinal resection in rats.

Total parenteral nutrition (TPN) alters both specific and nonspecific immune functions, resulting in immunosuppression. Short-chain fatty acids have been shown to improve the adaptive responses of the gut after surgery. The following study investigates the effects of adding short-chain fatty acids to TPN on the immune system after an 80% small bowel resection. Rats (237 +/- 3 g) were infused with either TPN (n = 25) or TPN supplemented with short-chain fatty acids (n = 26) for 3 or 7 days. Hematologic analysis was performed on peripheral blood and splenocytes were isolated to characterize cell phenotypes, natural killer cell cytotoxicity and to estimate proliferative response. The relative percent of T (CD3+) cells increased (p < .05) and the relative percent of macrophages decreased (p < .001, n = 13) in the spleens of the 3-day TPN-fed rats. By day 7, these differences disappeared. The natural killer cells from rats that were supplemented with short-chain fatty acids had higher (p < .0001) cytotoxic activity than the TPN groups at day 3. Mitogenic response did not differ between groups but were depressed compared with sham-treated rats. By day 7, rats on standard TPN had larger (p < .0001) spleens than all other groups. This group also had a higher total white blood cell count because of increased numbers of macrophages and neutrophils (p < .02). Short-chain fatty acids improve components of nonspecific immune responses and may be beneficial in reducing certain aspects of TPN-associated immunosuppression after major surgery.

A Total Parenteral Nutrition Solution Supplemented with a Nucleoside and Nucleotide Mixture Sustains Intestinal Integrity, but Does Not Stimulate Intestinal Function after Massive Bowel Resection in Rats

The effects of supplementing a total parenteral nutrition solution with a nucleoside and nucleotide mixture on mucosal adaptive processes after massive bowel resection were studied. Male Wistar rats (n = 30) underwent 80% small intestine resection, were randomized into two groups and received either standard total parenteral nutrition (TPN) or TPN supplemented with a nucleoside and nucleotide mixture (2.5 mL·kg-1·d-1). An additional five rats, fed a nonpurified diet and not resected, were used as controls. After 4 or 7 d, rats were killed and samples were collected for mucosal indices and intestinal enzymatic activities (disaccharidases and diamine oxidase). After massive small bowel resection and TPN, residual jejunal mucosal wet weights, villus heights, protein and RNA contents on d 4 and 7, and total wet weights and DNA contents on d 7 were significantly lower than in the control group. Administration of the nucleoside and nucleotide mixture resulted in significantly higher residual jejunal total and mucosal weights, protein, DNA, RNA contents, and the ratio of proliferating cell nuclear antigen positive cells per crypt than did the standard TPN solution on d 7. However, disaccharidase and diamine oxidase activities were not affected by supplementation with the nucleoside and nucleotide mixture. Our data suggest that supplementation of a nucleoside and nucleotide mixture to a TPN solution can attenuate the initial mucosal atrophy and improve intestinal cell turnover after massive bowel resection, but the supplementation has little effect on enterocyte enzymatic activities.

Glutamine-Enriched Total Parenteral Nutrition Enhances Plasma Glutathione in the Resting State

Glutathione (GSH) is the major intracellular antioxidant and is essential to normal cell function and replication. Cysteine and other thiol compounds have been considered rate-limiting for GSH biosynthesis, but recent studies have demonstrated that glutamine (GLN) becomes essential during metabolic stress to replete tissue GSH levels which have become depleted. To determine the role of GLN supplementation in the resting, nonstressed state, we studied three groups of Wistar rats. The animals were catheterized and randomly assigned to one of three groups: (1) chowad libitumgroup receiving iv saline (control), (2) standard total parenteral nutrition (STA-TPN) group, and (3) glutamine-enriched TPN (GLN-TPN) group. The intravenously fed animals received no rat chow. The infusions were administered at a rate of 2.2 ml/hr for 4 days and all animals were harvested on the fifth day of study. The GLN-TPN group had a significantly higher plasma GSH level than STA-TPN or control animals (P< 0.01). The hepatic concentration of GSH and the oxidized GSH/reduced GSH were similar in all groups. GLN-TPN had a significantly lower plasma ALT level than the control group (P< 0.05). The control group had a significantly higher ALP level than STA-TPN and GLN-TPN animals (P< 0.01). There were no significant differences in other measures of hepatic functions among the three groups. Our data demonstrate that in this model GLN-enriched TPN enhances plasma GSH concentrations, while maintaining hepatic GSH stores. This suggests that GSH turnover is altered during glutamine-enriched TPN, which may explain how dietary GLN supplementation enhances tissue antioxidant capacity.

The Effect of Glutamine Administration on Intestinal Glutamine Content

The small intestine has been identified as an important site of metabolism of glutamine. The impairment of gut mucosa integrity during total parenteral nutrition (TPN) has been ascribed to a diminished supply of glutamine, due to the lack of glutamine in standard TPN. In addition, nutritional depletion diminishes glutamine availability in the intestine. The uptake of glutamine in the gut is dependent on the plasma glutamine concentration. This study was performed to observe changes in plasma and mucosa amino acid content during infusion of standard TPN and during infusion of TPN supplemented with glutamine. Twenty patients were randomly allocated to an experimental group (GTPN, TPN containing 0.23 g glutamine/kg·day) and a control group (CTPN, standard TPN). Patients received the iso-nitrogenous and iso-caloric TPN during 10–14 days. After an overnight fast, before TPN was started, biopsies were taken from the duodenum. Amino acid concentrations were determined in the biopsies. Blood was taken for routine laboratory measurements and amino acid determination. This procedure was repeated on the last day of TPN infusion. Plasma glutamine in the GTPN group rose about 25% whereas plasma glutamine concentrations in the CTPN group remained unchanged. Mucosa glutamine rose with about 75% in the GTPN group whereas in the CTPN group no increase was observed. The rise of total plasma and mucosa amino acids was equal in both groups. The rise in plasma and mucosa glutamine was limited to nutritionally depleted patients. In conclusion, parenteral glutamine administration increases plasma and subsequently mucosa glutamine, specifically in depleted patients.

The enhanced effect of parenteral nutrition on hepatotoxicity

Recent studies have demonstrated that enteral feedings are associated with decreased morbidity and mortality when compared with parenteral feedings. In this study, we hypothesized that (1) route of feeding affects morbidity and mortality in a model of drug-induced hepatotoxicity and (2) glutamine and polymyxin B, which have been reported to reduce bacterial translocation, attenuate this effect when TPN is used. Male virus-free Wistar rats were divided into six groups receiving: (1) ad libitum chow infused with intravenous (IV) saline (Chow), (2) standard total parenteral nutrition solution administered via gastrostomy (Enteral), (3) standard total parenteral nutrition infused via a central catheter (TPN), (4) standard TPN containing polymyxin B (TPN-PolyB), and (5) glutamine-enriched TPN (TPN-GLN). A final group of animals was not manipulated but harvested at time 0 to serve as controls. The dose of polymyxin B used in this study has previously been shown to significantly reduce bacterial translocation. After 4 d of feeding, all rats received 5% dextrose infusion after an intraperitoneal (IP) injection of acetaminophen (ACM). Rats were sacrificed 0, 6, and 24 h after ACM administration. The TPN group had a lower liver glutathione level after 6 and 24 h, greater levels of liver enzymes after 24 h, and a lower survival rate after 24 h compared with Chow. The Enteral group had less morbidity than TPN but greater morbidity than Chow. Addition of polymyxin B or glutamine had a minimal effect on morbidity or mortality when compared to the TPN group. We conclude that rats receiving IV nutrition have greater morbidity and mortality following a standard hepatic insult than chow-fed rats. We speculate that alteration of microsomal cytochrome P-450 or drug clearance may be related to the benefits of providing nutrients by the gastrointestinal route.

Immunostimulation following fish oil-based parenteral nutrition in tumor-bearing rats.

Tumor-bearing (TB) and control rats were maintained for four to seven days on total parenteral nutrition (TPN) in which the lipid component (11.1% of total calories) was Intralipid or fish oil. Although no TB rats maintained on standard Intralipid-based TPN died prematurely in these experiments, one-third of the TB rats maintained on fish oil-based TPN died of bleeding complications by Day 4 of TPN infusion. The bleeding appeared to be due to the particle size in the fish oil emulsion, because a subsequent study employing a better emulsified TPN with smaller lipid particles exhibited fewer bleeding problems. Tumor growth, skeletal muscle atrophy, and gut hypoplasia were not reduced in the TB group maintained on fish oil-based TPN. However, immunosuppression observed in the Intralipid-based TPN group, as measured by mitogen response of cultured splenocytes, was significantly improved in the rats maintained on fish oil-based TPN. Levels of eicosapentaenoic acid were reduced in all rats receiving TPN. Although the hypothesized antitumor and anticachexia effects of fish oil administration were not realized, significant improvement in immunosuppression was noted. These results suggest that intravenously administered fish oil may have potential positive effects for the host.

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

Since tumor-bearing rats are deficient in glutamine, we investigated whether (1) glutamine and glutathione deficiency occur in tumor-bearing rats, (2) glutamine supplementation caused an increase of glutathione levels in host tissues and tumor, (3) glutamine enhances protein synthesis in host tissues, and (4) glutamine stimulated the tumor to synthesize protein and DNA. Male Donryu rats were randomized into four groups: (1) non-tumor-bearing rat (NTB) + standard total parenteral nutrition (STPN); (2) NTB + glutamine-supplemented TPN (GTPN); (3) tumor-bearing rat (TB) + STPN; (4) TB + GTPN. On day 0 AH109A rat hepatoma cells were subcutaneously injected into the backs of rats to induce tumor. The animals were maintained on TPN for 6 days from day 10 through day 15. On day 15, 1-14C-leucine was given by a 5-hour continuous infusion (2.0 microCi/h per rat) to determine the fractional synthesis rate and endogenous leucine production. The levels of glutamine and glutathione were measured by HPLC. the tumor DNA synthesis was estimated by bromodeoxyuridine labeling index. Tumor development led to a significant weight loss, but this weight loss was significantly lessened by glutamine supplementation because of an increase in muscle protein synthesis. Glutamine did not enhance tumor weight, protein, and DNA synthesis in the tumor. Tumor development caused a significant reduction of glutathione in the muscle, jejunum, and liver, but supplemented glutamine increased the levels of glutathione in the jejunum. Glutamine supplementation is beneficial in preventing deficiencies of glutamine and glutathione and in improving protein metabolism in tumor-bearing rats.

Effect of methionine-deprived total parenteral nutrition on tumor protein turnover in rats.

Previous studies have shown that a methionine-lacking diet inhibited tumor growth in rats. The aim of this study was to determine how methionine free total parenteral nutrition (MTPN) can result in the inhibition of tumor growth on tumor protein metabolism in rats. On day 0, AH109A rat ascites hepatoma cells were implanted subcutaneously into male Donryu rats (n = 68, body weight, 200-225 gm). On day 10, a catheter for total parenteral nutrition (TPN) was placed and either MTPN or standard TPN solution was given for 5 days. On day 15, 1-14C-leucine was infused continuously to measure tumor protein synthesis. Tumor proteolysis was calculated from tumor regional blood flow, using the 85Sr-microsphere injection method. 1) Tumor weight was reduced with MTPN. 2) MTPN did not affect tumor protein synthesis, probably because endogenous methionine production was increased with MTPN (87.3 +/- 13.5 mumole methionine/kg/hour vs. 218.6 +/- 29.5, P < 0.01); however, MTPN caused an increase of tumor proteolysis (2.68 +/- 0.53 mumole leucine/g/hour vs. 3.79 +/- 0.73, P < 0.05). The enhanced tumor protein breakdown contributed to the inhibition of tumor growth that was found with the rats given the methionine free diet.

Effect of Glutamine Supplement and Hepatectomy on DNA and Protein Synthesis in the Remnant Liver

One of the physiological roles of glutamine is as a precursor for DNA synthesis. The aims of this study were to determine (1) whether glutamine-supplemented total parenteral nutrition (TPN) enhanced DNA and protein synthesis in the liver and (2) whether glutamine uptake was increased following partial hepatectomy in rats. Male Donryu rats ( n = 59; body weight, 250-275 g) were randomized into four groups: (1) sham operation + standard TPN solution (C-STPN); (2) C + glutamine-supplemented TPN (C-GTPN); (3) 70% partial hepatectomy + STPN (H-STPN); (4) partial hepatectomy + GTPN (H-GTPN). On Day 0, rats underwent either a sham operation or 70% partial hepatectomy and concomitantly were catheterized in the jugular vein. TPN was begun immediately after the surgery. GTPN was isocaloric and isonitrogenous with STPN and 25% of total nitrogen was given as glutamine. On Day 2, the animals were sacrificed after either a continuous infusion of 1- 14C-leucine or a bolus iv injection of bromodeoxyuridine. The rate of hepatic regeneration was enhanced with glutamine supplementation (H-STPN, 60.8 ± 1.6% vs H-GTPN, 66.3 ± 2.0, P < 0.05) due to an increase in protein synthesis in the liver (H-STPN, 134.0 ± 10.3%/day vs H-GTPN, 160.9 ± 6.9, P < 0.05) and DNA synthesis in hepatocytes (H-STPN, 23.1 ± 2.5% vs H-GTPN, 31.4 ± 2.9, P < 0.05). The uptake of glutamine by the liver was increased following hepatectomy with GTPN supplementation. In conclusion, glutamine supplement and partial hepatectomy stimulated glutamine uptake in the liver and this results in an enhancement of protein and DNA synthesis in the remnant liver.

Interrelation of intracellular proteases with total parenteral nutrition-induced gut mucosal atrophy and increase of mucosal macromolecular transmission in rats.

Total parenteral nutrition (TPN) is known to induce mucosal atrophy and to increase macromolecular transmission of the small intestine. The potential participation of various proteases in that process was investigated. Male Wistar rats were randomly divided into two groups: the TPN group (n = 11) received a standard TPN (250 kcal/kg per day, 1.78 g nitrogen/kg per day) and the FED group (n = 10) received a standard rat food for 1 week. This was followed by an examination of gut macromolecular transmission of fluorescein isothiocyanate dextran 70,000 (FITC-dextran) after intragastric injection and of the activities of gut mucosal cathepsins B, H, and L and of proteasome. Mucosal wet weight and protein content decreased significantly by TPN for 1 week. In both groups, the activities of all proteases in the ileum were significantly greater than in the jejunum. In the TPN group, cathepsin L and H activities in the ileum, and cathepsin B activity in both the jejunum and the ileum, were greater than those in the FED group. The portal concentration of FITC-dextran was higher than arterial and venous concentrations in the both groups. In the TPN group, the portal FITC-dextran concentration increased significantly compared with the FED group. In conclusion, active proteolysis is not associated with TPN-induced mucosal atrophy. Cathepsins activities in the ileum increase as a result of TPN. Interrelationship is implicated between increase of lysosomal protease activity and the deterioration of the intestinal barrier function, which permits macromolecular transmission.

Prevention of fatty liver and maintenance of systemic valine depletion using a newly developed dual infusion system.

Valine-depleted amino acid imbalance, while having a suppressive effect on tumor growth, may induce fatty liver. We administered a valine-depleted total parenteral nutrition (TPN) solution by the central venous route to non-tumor-bearing rats and examined the time course of the development of fatty liver. In an attempt to prevent this condition, we administered a continuous infusion of low concentrations of valine via the portal vein simultaneously with administration of central venous valine-depleted nutrition for 4 days. A marked accumulation of triglyceride was observed in the liver on day 4 of the administration of valine-depleted nutrition. It is speculated that such accumulation is the cause of fatty liver. The level of valine in the peripheral blood began to decrease soon after administration was begun and resulted in a state of systemic valine deficiency. Rats given 25% or more of the valine concentration in the standard TPN solution via the portal vein simultaneously with the administration of central venous valine-depleted nutrition, had a triglyceride level similar to that of the control group. The group given 50% or less of the valine concentration had a level of valine in the peripheral blood as low as that of the valine-depleted group, indicating the maintenance of a valine-deficient state. Administration of low concentrations of valine via the portal vein simultaneous with central venous administration of valine-depleted TPN solution may prevent fatty liver.

Glutamine Prevents the Biliary Lithogenic Effect of Total Parenteral Nutrition in Rats

Long-term total parenteral nutrition (TPN) is known to be associated with pigment gallstones. The objectives of this study were to identify the lithogenic effects of TPN and to determine whether glutamine (GLN)-enriched TPN can prevent such changes. Eighteen male Wistar rats were randomly divided into three groups of six animals. A central line was inserted via the jugular vein. The CHOW group received an infusion of saline and chow ad libitum; the TPN group received a standard TPN solution; the GLN group received TPN solution identical to the TPN group except for the addition of 2% glutamine. Diets were isonitrogenous and isocaloric and fed for 7 days. On Day 7, following laparotomy, the bile duct was cannulated, and bile flow was measured and collected for assay of total and unconjugated bilirubin (TB & UCB) and of total and ionized calcium (TCa & iCa). Caval blood was obtained for liver function studies. The results demonstrated that the hepatic bile flow was decreased in the TPN group compared with the CHOW and the GLN groups. The bilirubin concentration of bile, especially unconjugated bilirubin, in the TPN group was significantly higher when compared with the CHOW and GLN groups ( P < 0.01). The ionized calcium concentration of bile in the TPN group was also increased significantly when compared with the CHOW and GLN groups ( P < 0.05). From these data, we conclude that TPN induces lithogenic effects in hepatic bile, including increased bilirubin and calcium concentrations and decreased hepatic bile flow. Addition of glutamine to the TPN solution prevents these lithogenic changes.