Hypertonic saline-enhanced postburn gut barrier failure is reversed by inducible nitric oxide synthase inhibition.
OBJECTIVE
To determine whether inhibition of inducible nitric oxide synthase to stabilize endothelial permeability and to retain hypertonic saline in the vascular space will ameliorate burn-induced gut barrier dysfunction.


METHODS
Prospective, experimental study.


METHODS
Research laboratory at a university hospital.


METHODS
Thermal injury models in the rat.


METHODS
In experiment 1, specific pathogen free rats underwent 3% total body surface area burn or sham burn and were given 7.5 mL/kg hypertonic saline (7.5% NaCl), 7.5 mg/kg saline, or 50 mL/kg saline (nearly equal sodium load with hypertonic saline) in the right femoral vein for 15 mins for fluid resuscitation at 0, 4, or 8 hrs after burn. In experiment 2, S-methylisothiourea (7.5 mg/kg, intraperitoneally), a specific inducible nitric oxide synthase inhibitor, was given immediately after burn to rats from different groups as in experiment 1. At 24 hrs after burn, the intestinal mucosa was assayed for myeloperoxidase activity and lipid peroxidation, the distribution of fluorescein isothiocyanate-dextran across the lumen of the small intestine was determined, and bacterial translocation to the mesenteric lymph nodes and ileum histology were also examined.


RESULTS
Burn induced significant increases in intestinal mucosa inducible nitric oxide synthase expression, myeloperoxidase activity, lipid peroxidation, intestinal permeability, bacterial translocation to mesenteric lymph nodes, and villi sloughing in rats. Hypertonic saline administration at 0 or 4 hrs after burn worsened intestinal mucosa lipid peroxidation, neutrophil sequestration, intestinal permeability, and villi sloughing compared with those of burn + 7.5 mg/kg saline and burn + 50 mL/kg saline rats. To the contrary, burn + S-methylisothiourea rats with hypertonic saline injection at 4 or 8 hrs after burn showed an improvement of gut barrier function compared with burn + S-methylisothiourea + 7.5 mg/kg saline and burn + S-methylisothiourea + 50 mL/kg saline rats. Administration of hypertonic saline at 8 hrs after burn and S-methylisothiourea injection also significantly attenuated the bacterial translocation to mesenteric lymph nodes and villi sloughing.


CONCLUSIONS
Using hypertonic saline as a resuscitation fluid in early burn shock markedly augmented the thermal injury-induced intestinal mucosa neutrophil deposition, lipid peroxidation, and intestinal hyperpermeability. Inhibition of inducible nitric oxide synthase not only significantly attenuated neutrophil deposition and mucosa lipid peroxidation but also reversed the deteriorating effects of hypertonic saline on thermal injury-induced gut barrier dysfunction and bacterial translocation.
Chen
Lee-Wei
LW
Department of Surgery, Kaohsiung Veterans General Hospital, National Yang-Ming Medical University, Taipei, Taiwan.
Hwang
Bonnie
B
Wang
Jyh-Seng
JS
Chen
Jin-Shyr
JS
Hsu
Ching-Mei
CM
D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects*; D001483:Base Sequence; D002056:Burns / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D007550:Isothiuronium / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010539:Permeability / Q000187:drug effects; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D012462:Saline Solution, Hypertonic / Q000494:pharmacology*; D012680:Sensitivity and Specificity
D012333:RNA, Messenger; D012462:Saline Solution, Hypertonic; D007550:Isothiuronium; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat