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Am J Physiol Gastrointest Liver Physiol 290: G616-G623, 2006. First published October 27, 2005; doi:10.1152/ajpgi.00248.2005
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INFLAMMATION/IMMUNITY/MEDIATORS

Differential induction of PPAR-{gamma} by luminal glutamine and iNOS by luminal arginine in the rodent postischemic small bowel

N. Sato,1 F. A. Moore,1 B. C. Kone,2 L. Zou,2 M. A. Smith,1 M. A. Childs,1 S. Moore-Olufemi,1 S. G. Schultz,3 and R. A. Kozar1

Departments of 1Surgery, 2Medicine, and 3Integrative Biology and Pharmacology, Houston School of Medicine, University of Texas, Houston, Texas

Submitted 31 May 2005 ; accepted in final form 7 October 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Using a rodent model of gut ischemia-reperfusion (I/R), we have previously shown that the induction of inducible nitric oxide synthase (iNOS) is harmful, whereas the induction of heme oxygenase 1 (HO-1) and peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) is protective. In the present study, we hypothesized that the luminal nutrients arginine and glutamine differentially modulate these molecular events in the postischemic gut. Jejunal sacs were created in rats at laparotomy, filled with either 60 mM glutamine, arginine, or magnesium sulfate (osmotic control) followed by 60 min of superior mesenteric artery occlusion and 6 h of reperfusion, and compared with shams. The jejunum was harvested for histology or myeloperoxidase (MPO) activity (inflammation). Heat shock proteins and iNOS were quantitated by Western blot analysis and PPAR-{gamma} by DNA binding activity. In some experiments, rats were pretreated with the PPAR-{gamma} inhibitor G9662 or with the iNOS inhibitor N-[3(aminomethyl)benzyl]acetamidine (1400W). iNOS was significantly increased by arginine but not by glutamine following gut I/R and was associated with increased MPO activity and mucosal injury. On the other hand, PPAR-{gamma} was significantly increased by glutamine but decreased by arginine, whereas heat shock proteins were similarly increased in all experimental groups. The PPAR-{gamma} inhibitor G9662 abrogated the protective effects of glutamine, whereas the iNOS inhibitor 1400W attenuated the injurious effects of arginine. We concluded that luminal arginine and glutamine differentially modulate the molecular events that regulate injurious I/R-mediated gut inflammation and injury. The induction of PPAR-{gamma} by luminal glutamine is a novel protective mechanism, whereas luminal arginine appears harmful to the postischemic gut due to enhanced expression of iNOS.

gut ischemia-reperfusion; peroxisome proliferator-activated receptor-{gamma}; inducible nitric oxide synthase

SHOCK-INDUCED MESENTERIC ischemia-reperfusion (I/R) has been invoked to play a pivotal role in postinjury multiple organ failure (17). We have developed a superior mesenteric artery occlusion (SMAO) model to study the molecular events that regulate gut inflammation and injury after shock. Our research focus has evolved into studying how standard therapies commonly used in the intensive care unit can be modified to protect the postischemic gut. One such therapy that we are studying in the laboratory and using clinically is the administration of isolated intraluminal nutrients to prevent injury or hasten the repair process. We have demonstrated that luminal nutrients have differential effects on gut injury and function that are partially explained by the degree of metabolic stress imposed on the gut by the individual nutrients (27, 28). More recently, we have shown that nutrients can differentially modulate I/R-induced inflammation (34). The molecular events responsible for these differences, however, have not been investigated. On the basis of previous observations that inducible nitric oxide (NO) synthase (iNOS) was associated with impaired intestinal transit (19) (one marker of gut dysfunction) and peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) and heme oxygenase 1 (HO-1) and was preferentially induced by protective strategies (such as intraischemic hypothermia, hypertonic saline, {alpha}-melanocyte-stimulating hormone, and cyclooxygenase-2 inhibition) (3, 18, 20, 35) in a rodent model of gut I/R, we hypothesized that the luminal nutrients arginine and glutamine would differentially modulate the pro- and anti-inflammatory mediators activated by gut I/R. PPARs are transcription factors that belong to the same family of nuclear receptors as steroid and thyroid hormone receptors and function as regulators of lipid and lipoprotein metabolism and glucose homeostasis as well as influence cellular proliferation, differentiation, and apoptosis (11). PPAR-{gamma} has recently been recognized as an endogenous regulator of intestinal inflammation (8, 30). Because gut I/R is known to induce inflammation, PPAR-{gamma} may play a critical role in shock-induced gut protection.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Rodent Model of Mesenteric I/R

All procedures performed were protocols approved by the University of Texas Houston Medical School Animal Welfare Committee. Male Sprague-Dawley rats weighing 250–300 g were fasted with free access to water overnight before laparotomy. Operative procedures were performed using sterile techniques under general anesthesia with isoflurane-inhaled anesthetic.

An upper midline laparotomy was performed, and the jejunum was identified 5 cm distal to the ligament of Treitz. An 8-cm intestinal sac was created in each animal by occluding the lumen of the bowel with 3-0 silk ligatures, as previously described (28). Sacs were filled with either 60 mM glutamine, 60 mM arginine, or 30 mM magnesium sulfate (nonabsorbable osmotic control). Sixty millimolar approximates the amount of glutamine and arginine found in commercially available immune-enhancing enteral diets. SMAO was carried out for 60 min, based on a previous study that demonstrated consistent differences in mucosal injury between groups with no measurable mortality (26). After removal of the clamp, the incision was closed and rats were allowed to awaken and were observed for 6 h. We (20) have previously demonstrated that mesenteric I/R results in maximal activation of NF-{kappa}B in the postischemic small bowel at 6 h. Sham animals underwent the identical procedure but without placement of the clamp on the superior mesenteric artery. One group of animals underwent SMAO alone with no enteral sac as an additional control. An overview of the experimental design is shown in Fig. 1.


Figure 1
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  		Fig. 1. Overview of experimental design. iNOS, inducible nitric oxide synthase; PPAR-{gamma}, peroxisome proliferator-activated receptor-{gamma}; HO-1, heme oxygenase 1; HSP70, heat-shock protein 70; SMA, superior mesenteric artery.

 
Experiment 1: Inflammatory Mediator Expression in the Postischemic Small Bowel

Protein expression of the proinflammatory mediator iNOS and the anti-inflammatory mediators PPAR-{gamma} and HO-1 were measured after 60 min of ischemia and 6 h of reperfusion and exposure to the enteral nutrients.

Preparation of nuclear and cytoplasmic extracts. Nuclear and cytoplasmic extracts from the full-thickness jejunum were prepared by the method of Deryckere and Gannon (10) as described by our group (34).

DNA-binding activity of PPAR. The DNA-binding activity of PPAR in the nuclear extracts was determined by electrophoretic mobility shift assay. The PPAR consensus oligonucleotide 5'-GAA AAG TAG GTC AAA GGT GA-3' (Santa Cruz Biotechnology, Santa Cruz, CA) was end labeled with [{gamma}-32P]ATP T4 polynucleotide kinase. Nuclear protein (10 µg) was incubated for 20 min with gel shift binding buffer [10 mM Tris (pH 7.5), 50 mM NaCl, 1 mM dithiothreitol, 1 mM EDTA, 5% glycerol, and 1 µg of poly(dI-dC)] and 1.0 µl of labeled probe. Gel loading buffer was added to the mixture, and samples were electrophoresed on a nondenaturing 5% polyacrylamide gel. Gels were dried and analyzed by image-analysis software (Optimas 6.1, media Cybernetics, Silver Spring, MD) and are expressed in arbitrary units. As a control, a mutant PPAR oligonucleotide was similarly labeled with [{gamma}-32P]ATP T4 polynucleotide kinase. No DNA-binding activity was detected (data not shown).

Heat shock proteins and iNOS immunoreactivity. Heat shock protein (HSP; HO-1 and HSP-70) and iNOS protein expression by Western immunoblot was performed as previously described (2, 19). In brief, jejunal cytoplasmic extracts were loaded in each well, and the proteins were separated by SDS-PAGE. Proteins were then transferred to nitrocellulose membranes and then treated with 5% nonfat milk in Tris-buffered saline solution [20 mM Tris·HCl, 130 mM NaCl (pH 7.6), and 0.1% Tween 20] and incubated at 4°C overnight with site-directed mouse monoclonal anti-HO-1 or HSP-70 (Stressgen, Victoria, British Columbia, Canada) or polyclonal anti-iNOS antibody (BD Biosciences Pharmingen). The membranes were washed with Tris-buffered saline solution and incubated with horseradish peroxidase-conjugated secondary antibody to identify HSP or iNOS according to an enhanced chemiluminescence Western blotting detection system (Amersham Life Science, Piscataway, NJ). Autoradiograms were then analyzed using image-analysis software (Optimal 6.1) and are expressed in arbitrary units.

Myeloperoxidase activity. Myeloperoxidase (MPO) activity was measured as an index of gut leukocyte infiltration. Cytoplasmic extracts from full-thickness jejunum were diluted 1:5 in buffer A (0.6% Nonidet P-40, 150 mM NaCl, 10 mM HEPES, 1 mM EDTA, 0.5 mM PMSF, and 30 µl/ml protease inhibitor cocktail). Ten microliters of each sample were then added to the wells of 96-well plates and incubated with 100 µl tetramethyl bezidine microwell peroxidase substrate at room temperature for 20 min. The reaction was stopped with 100 µl of 1.8 M sulfuric acid. Optical density was measured at 450 nm with an ELISA plate reader. Assays were performed in duplicate, and the results were normalized for protein content.

Histology. Gut mucosal injury was assessed in full-thickness segments of the jejunum that were immersed in 10% formalin for at least 24 h, imbedded in paraffin wax, cut into 5-µm sections, and then stained with hematoxylin and eosin. Tissues were examined under a light microscope by a blinded, experienced observer and scored using a mucosal grading scale (0–5) as described by Chiu et al. (7) with grade 0 representing normal mucosal and grade 5 revealing disintegration, hemorrhage, and ulceration.

Experiment 2: PPAR-{gamma} Inhibition by GW9662

GW9662 is an irreversible antagonist of PPAR-{gamma}. It is 10- to 600-fold less potent in binding PPAR-{alpha} and PPAR-{delta}, respectively, and does not effect transcription of these subtypes. In the second set of experiments, GW9662 was administered intravenously (1 mg/kg) 30 min before laparotomy and then at 1 mg/kg ip at the onset of reperfusion (1, 22). Control animals received the equivalent volume of vehicle. Jejunal nutrient sacs were created and filled with either 60 mM glutamine or arginine, after which rats underwent 60 min of SMAO and 6 h of reperfusion. The jejunum was harvested for measurement of iNOS protein expression, MPO activity, and gut injury as described for experiment 1.

Experiment 3: iNOS Inhibition by N-[3(aminomethyl)benzyl]acetamidine

In the third set of experiments, N-[3(aminomethyl)benzyl]acetamidine (1400W), a selective inhibitor of iNOS, was directly administered into the nutrient sac (20 mg/kg) 30 min before laparotomy (15). Because 1400W is a competitive inhibitor of arginine, intravenous administration at nontoxic concentrations was not sufficient to inhibit enteral arginine absorption (results not shown). Control animals received the equivalent volume of vehicle. Jejunal nutrient sacs were created and filled with either 60 mM glutamine or arginine, after which rats underwent 60 min of SMAO and 6 h of reperfusion. The jejunum was harvested for measurement of iNOS protein expression, MPO activity, and gut injury as described for experiment 1.

Statistical Analysis

Data are expressed as means ± SE, with n ≥ 6 animals per group. Raw data for DNA-binding activity and protein expression were normalized with the SMAO group being assigned an arbitrary value of 100. Data were then analyzed by one-way ANOVA, and individual group means were compared using Tukey's multiple-group comparison test. P values of <0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Experiment 1: Inflammatory Mediator Expression in the Postischemic Small Bowel

Arginine increases, whereas glutamine decreases, iNOS protein expression in the postischemic small bowel. Figure 2A depicts a representative immunoblot, and Fig. 2B depicts the summary densitometry for iNOS protein expression. There was a low detectable level of iNOS in shams (34.0 ± 0.3 sham magnesium sulfate, 35.0 ± 0.5 sham arginine, and 37.7 ± 0.3 sham glutamine; no significant difference among groups). SMAO alone (100 ± 1.9) and I/R controls (98.0 ± 2.4) exhibited greater iNOS levels compared with shams. Of note, iNOS levels in I/R arginine animals were even greater (215 ± 18.4), whereas in I/R glutamine animals, they were less (71.0 ± 6.6) compared with the other experimental I/R groups.


Figure 2
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  		Fig. 2. iNOS protein expression in the postischemic small bowel following exposure to enteral nutrients. A: representative immunoblot. B: summary densitometry. Results are expressed as means ± SE (n ≥ 6 animals/group). a,b,c,dMeans with different letters are significantly different. SMAO, SMA occlusion; I/R, ischemia-reperfusion.

 
Arginine and glutamine do not effect HSP expression in the postischemic small bowel. Figure 3A depicts representative immunoblots for HO-1 and HSP-70 expression, and the summary densitometry is shown in Fig. 3B. For both HO-1 and HSP-70, SMAO alone and I/R controls demonstrated significantly greater levels compared with shams, but arginine and glutamine groups exhibited no differential modulatory effects.


Figure 3
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  		Fig. 3. HO-1 and HSP70 protein expression in the postischemic small bowel following mesenteric I/R and enteral nutrients. A: representative immunoblot of HO-1 and HSP70 expression. B: summary densitometry. a,b,A,BMeans with different letters are significantly different; capital vs. lowercase letters differentiate the 2 different experiments (HO-1 vs. HSP70).

 
Arginine decreases, whereas glutamine increases, PPAR DNA-binding activity in the postischemic small bowel. Figure 4A depicts a representative electrophoretic shift mobility assay, and Fig. 4B depicts the summary densitometry for PPAR DNA-binding activity. SMAO alone (100.0 ± 4.9) and I/R controls (98.4 ± 7.7) exhibited significantly greater PPAR DNA-binding activity compared with shams (39.9 ± 1.3 sham magnesium sulfate, 40.8 ± 0.2 sham arginine, and 41.8 ± 0.5 sham glutamine; no significant difference among groups). I/R arginine had lower activity of PPAR (53.6 ± 10.5), comparable with shams, whereas glutamine increased PPAR activity (165 ± 19.4) compared with all other experimental groups.


Figure 4
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  		Fig. 4. PPAR-{gamma} binding activity in the postischemic small intestine following exposure to enteral nutrients. A: representative immunoblot. B: summary densitometry. Results are expressed as means ± SE (n ≥ 6 animals/group). a,b,cMeans with different letters are significantly different.

 
Arginine increases gut inflammation. MPO was measured as an index of leukocyte infiltration (Table 1). Shams had low levels of MPO that were significantly increased by SMAO and I/R controls as well as by I/R glutamine. Of note, I/R arginine markedly increased MPO activity compared with all other experimental groups.


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  		Table 1. Gut inflammation and injury in the postischemic small bowel

 
Glutamine prevents mucosal injury. Shams demonstrated normal histology (Table 2). Small bowel mucosal injury was significantly increased in SMAO and I/R controls. Despite greater inflammation, I/R arginine did not exhibit greater mucosal injury, but I/R glutamine protected against injury, with scores comparable with shams. Representative photomicrographs of the postischemic small bowel are shown in Fig. 5.


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  		Table 2. iNOS protein expression, inflammation, and injury in the postischemic small bowel following pretreatment with GW9662

 

Figure 5
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  		Fig. 5. Representative photomicrographs of postischemic small bowel following exposure to enteral arginine (left; Chiu 4) and glutamine (right; Chiu 2). Magnification: x10.

 
Experiment 2: PPAR-{gamma} Inhibition by GW9662

GW9662 decreases PPAR binding activity in the presence of glutamine. To confirm that GW9662 was indeed inhibiting PPAR, binding activity was determined following administration of GW9662. Figure 6A depicts a representative immunoblot, and Fig. 6B depicts the summary densitometry following GW9662 administration. The increase in PPAR binding activity in the presence of glutamine (153.4 ± 12.6) was abrogated by pretreatment with GW9662 (104.7 ± 4.7) and was comparable with I/R alone (100 ± 4.), suggesting that glutamine was acting as a PPAR-{gamma} ligand.


Figure 6
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  		Fig. 6. PPAR-{gamma} binding activity following GW9662 administration. A: representative immunoblot. B: summary densitometry. Results are expressed as means ± SE (n ≥ 6 animals/group). a,bMeans with different letters are significantly different.

 
GW9662 increases iNOS protein expression in the presence of glutamine. Figure 7 depicts a representative immunoblot, and Table 2 depicts the summary densitometry following pretreatment with GW9662 and gut I/R. Sham animals expressed low levels of iNOS, which were higher in the glutamine I/R group but further significantly elevated by GW9662 in I/R glutamine animals. As expected, iNOS levels were significantly higher in I/R arginine animals, and expression was not altered by GW9962.


Figure 7
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  		Fig. 7. Representative immunoblot of iNOS protein expression in the postischemic small bowel following pretreatment with GW9662.

 
GW9962 increases gut inflammation in the presence of glutamine. Similar to iNOS, GW9662 did not alter MPO activity in shams (Table 2). MPO was increased by I/R glutamine but further increased by GW9662. As with iNOS expression, MPO activity was increased by I/R arginine but not changed by GW9662 pretreatment.

GW9962 increases gut injury in the presence of glutamine. Similar to iNOS and MPO, mucosal histology was not altered by GW9662 in shams (Table 2). Injury was increased by glutamine and was further increased by GW9662 in I/R glutamine animals. Injury in I/R arginine animals increased compared with I/R glutamine but was not changed by GW9662 pretreatment.

Experiment 3: iNOS Inhibition by 1400W

1400W decreases iNOS protein expression in the presence of arginine. Figure 8 depicts a representative immunoblot, and Table 3 depicts the summary of densitometry following 1400W administration. Shams had low levels of iNOS expression that were similarly elevated in I/R glutamine alone and 1400W I/R glutamine animals. I/R arginine markedly increased iNOS expression, which was significantly decreased by 1400W.


Figure 8
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  		Fig. 8. Representative immunoblot of iNOS protein expression in the postischemic small bowel following pretreatment with N-[3(aminomethyl)benzyl]acetamidine (1400W).

 

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  		Table 3. iNOS protein expression, inflammation, and injury in the postischemic small bowel following pretreatment with 1400W

 
1400W decreases gut inflammation in the presence of both arginine and glutamine. 1400W did not alter MPO activity in shams (2.0 ± 0.3 ng/mg protein vehicle sham and 2.1 ± 0.3 ng/mg protein 1400W sham). MPO was increased by glutamine alone following gut I/R (3.7 ± 0.4 ng/mg protein vehicle I/R glutamine) but was lessened by 1400W (3.0 ± 0.1 ng/mg protein I/R glutamine + 1400W). Similar to iNOS expression, MPO activity was markedly increased by arginine following gut I/R (11.4 ± 1.0 ng/mg protein) but was significantly lessened by 1400W pretreatment (4.65 ± 0.8 ng/mg protein), comparable with glutamine I/R animals.

1400W decreases mucosal injury in the presence of both arginine and glutamine. 1400W did not alter mucosal injury in shams (0.8 ± 0.3 vehicle sham and 0.6 ± 0.3 1400W sham). Mucosal injury was lessened by 1400W in I/R glutamine animals (1.3 ± 0.2) compared with I/R glutamine alone (2.0 ± 0.0). Injury in I/R arginine animals was increased compared with I/R glutamine; however, it was lessened by pretreatment with 1400W (4.4 ± 0.2 vs 2.9 ± 0.6, respectively).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the current study, we have demonstrated that luminal arginine, but not glutamine, administered during mesenteric I/R is associated with increased expression of the proinflammatory mediator iNOS and associated with gut mucosal injury and inflammation. NO is a potent effector molecule involved in numerous physiological processes, including neurotransmission, the control of vascular tone, inflammation, and immunity. NO production is governed by the activity of three NOS isoforms. Both neuronal and endothelial NOS are generally expressed under basal conditions. iNOS, on the other hand, is quiescent in most tissues until it is transcriptionally activated (e.g., following gut I/R) to produce large amounts of NO (25). Although NO also has potential benefits (such as smooth muscle relaxation and vasodilatation), it appears to be functioning as an inflammatory mediator in this model (12, 40), particularly in the presence of arginine. High levels of NO can be toxic during reperfusion because NO reacts with superoxide to produce peroxynitrite, which is a highly toxic oxidant (37). NO levels could be further increased by arginine because it is a known precursor of NO. Fukatsu et al. (14) also demonstrated the proinflammatory effects of (intravenous) arginine during gut ischemia. Arginine primed and activated circulating myeloid cells and increased mortality in their rodent model of gut I/R. NO has also been shown to result in gut dysfunction in a model of intestinal manipulation (23). Others, however, have demonstrated protective effects of NO production via arginine in models of gut I/R and hemorrhagic shock (13, 21, 29, 41). The majority of these studies, however, have administered intravenous arginine and examined systemic effects of this agent. Little is known about the effects of arginine on the gut during conditions of hypoperfusion. The current data suggest, however, that arginine-induced iNOS is injurious to the postischemic gut.

We also demonstrated that the iNOS-specific inhibitor 1400W lessened the injurious effects of iNOS on postischemic gut inflammation and injury. Because iNOS was minimally increased in the I/R glutamine animals, the effects were not as pronounced as in the I/R arginine animals in which 1400W markedly attenuated the injurious effect of arginine. Because 1400W has no direct effect on iNOS protein expression (and as demonstrated in the I/R glutamine groups) (31), the decrease in iNOS in I/R arginine animals may be secondary to suppression of iNOS-mediated protein kinase G feedback to activator protein (AP)-1, a known upstream proinflammatory transcription factor that induces iNOS expression (16, 34). This novel mechanism warrants further investigation.

In response to gut I/R, anti-inflammatory mediators such as HO-1 are also activated that serve to limit local injury and hasten repair (24, 38, 39). Although HO-1 expression was enhanced in the current study following gut I/R, we were unable to demonstrate a differential induction of HO-1 by enteral nutrients. This is somewhat surprising in that other protective interventions in this model have consistently been linked to HO-1 induction (3, 18). Additionally, Wischmeyer et al. demonstrated enhanced expression of HSP70 and HSP25 by glutamine following septic shock and global ischemia (though not in the small intestine) (43, 44). In our model of intestinal I/R, similar to HO-1, expression of HSP70 was increased by SMAO, but no differential modulatory effect by enteral nutrients was observed.

We also showed for the first time that enteral glutamine induces the expression of PPAR-{gamma} following mesenteric I/R and that administration of GW9662 abrogates the protective effects of glutamine resulting in enhanced inflammation and injury and increased expression of the proinflammatory mediator iNOS. There are three distinct PPARs: {alpha}, {delta}, and {gamma}, each encoded by a separate gene and distributed in different tissues. The functions of PPAR-{alpha} and PPAR-{gamma} have been shown to control the expression of genes implicated in the inflammatory response via negative interference with proinflammatory pathways (such as NF-{kappa}B and AP-1), signal transducers and activators of transcription 1 (STAT1), and nuclear factor of activated T cells (NFAT) (6, 33). PPAR-{gamma} is expressed primarily in adipose tissue and the intestine and is activated by several ligands including antidiabetic glitazones as well as nonsteroidal anti-inflammatory agents leading to their potential role in inflammation (4, 5, 9). Our results suggest that glutamine is also a ligand for PPAR-{gamma}, because binding activity in the presence of glutamine was completely abrogated by pretreatment with GW9662. To confirm ligand-dependent binding by glutamine, similar experiments could be performed using a known PPAR-{gamma} ligand such as troglitazone. This oral antihyperglycemic agent not only inhibits hepatic gluconeogenesis but has been demonstrated to effect glutamine metabolism in rat mesangial cells as well (42). Once activated by ligand, PPAR heterodimerizes with the retinoid X receptor and binds to specific PPAR-responsive elements of DNA to promote transcription of a wide variety of genes (36). Others (32) have suggested that glutamine acts through ligand-independent mechanisms, such as via MAPK, although our results do not suggest that this pathway is active in our model of SMAO.

In conclusion, we have demonstrated that the immune-enhancing luminal nutrients arginine and glutamine differentially modulate the molecular events that regulate mesenteric I/R-induced gut inflammation and injury. Induction of PPAR-{gamma} represents a novel mechanism for luminal glutamine protection, whereas luminal arginine appears harmful in our model due to enhanced expression of iNOS.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Institutes of Health Grants KO8 GM-62975 (to R. A. Kozar) and P50 GM-38529 (to F. A. Moore).


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. Kozar, Univ. of Texas, 6431 Fannin, MSB 4.284, Houston, TX 77030 (e-mail: Rosemary.A.Kozar{at}uth.tmc.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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