Nitric oxide synthase inhibitor ameliorates oral total parenteral nutrition-induced barrier dysfunction.
The expression of inducible nitric oxide synthase (iNOS) is increased in the intestine and results in mucosal damage after endotoxin challenge. Although the oral administration of total parenteral nutrition (TPN) solution promotes bacterial translocation (BT) and increases the intestinal permeability, the role of NO in the nutrition-induced loss of mucosal barrier function remains unclear. The distribution of fluorescein isothiocyanate-dextran (FITC-dextran, 4400) across the lumen of small intestine in rat was examined to investigate the role of NOS activity on the intestinal permeability under oral TPN feeding. Fifty-one rats were randomly divided into 4 groups. Group I (control group) was fed with rat chow, group II received TPN solution orally. Groups III and IV received TPN solution supplemented with NOS inhibitors. On day 9, FITC-dextran was injected into the intestinal lumen. After 30 min, blood samples were taken from portal vein and analyzed for plasma FITC-dextran level by fluorescence spectrophotometry. Samples of small intestine were frozen and sectioned in a cryostat for morphological and NOS histochemical studies. Homogenates of small intestine were used for NOS activity measurement. The plasma level of FITC-dextran showed a significant increase (P < 0.05) in rats fed with oral TPN compared with the control ones. Supplement with NOS inhibitors significantly decreased the intestinal permeability in groups III and IV compared with group II. Similarly, the total NOS activities showed a significant 2-fold increase (P< 0.05) in group II, and NOS inhibitors decreased the elevated NOS activity. These data suggest that oral TPN feeding for 9 days leads to an increase in permeability to dextran and the total NOS activity of small intestine, and both induction of the intestinal permeability and NOS activity were inhibited by treatment with NOS inhibitors. Addition of S-methylisothiourea (SMT), an iNOS selective inhibitor, profoundly inhibited 66% of the induced iNOS activity (P < 0.05) and reduced 74% of the diet-induced increase in intestinal permeability (P < 0.05) in group II. The induced permeability change in rats receiving oral TPN is mainly due to the activity of intestinal mucosal iNOS. The induction of iNOS is an important mediator for intestinal barrier dysfunction. Administration of SMT, which specifically decreases iNOS activity, is useful in the prevention of diet-induced barrier failure.
Hsu
C M
CM
Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
Liu
C H
CH
Chen
L W
LW
D000284:Administration, Oral; D000818:Animals; D001284:Atrophy / Q000209:etiology / Q000517:prevention & control; D018988:Bacterial Translocation / Q000187:drug effects; D003911:Dextrans; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D007082:Ileum / Q000473:pathology; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010289:Parenteral Nutrition, Total / Q000009:adverse effects*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012996:Solutions / Q000008:administration & dosage / Q000009:adverse effects
D003911:Dextrans; D004791:Enzyme Inhibitors; D012996:Solutions; C015219:fluorescein isothiocyanate dextran; D007550:Isothiuronium; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C027744:S-methylisothiopseudouronium; D016650:Fluorescein-5-isothiocyanate; D019331:NG-Nitroarginine Methyl Ester