NOX, a novel nitric oxide scavenger, reduces bacterial translocation in rats after endotoxin challenge.
Endotoxemia promotes gut barrier failure and bacterial translocation (BT) by upregulating inducible nitric oxide synthase (iNOS) in the gut. We hypothesized that administration of a dithiocarbamate derivative, NOX, which scavenges nitric oxide (NO), may reduce intestinal injury and BT after lipopolysaccharide (LPS) challenge. Sprague-Dawley rats were randomized to receive NOX or normal saline via subcutaneously placed osmotic pumps before or after LPS challenge. Mesenteric lymph nodes, liver, spleen, and blood were cultured 24 h later. Transmucosal passage of Escherichia coli C-25 or fluorescent beads were measured in an Ussing chamber. Intestinal membranes were examined morphologically for apoptosis, iNOS expression, and nitrotyrosine immunoreactivity. NOX significantly reduced the incidence of bacteremia, BT, and transmucosal passage of bacteria and beads when administered before or up to 12 h after LPS challenge. LPS induced enterocyte apoptosis at the villus tips where bacterial entry was demonstrated by confocal microscopy. NOX significantly decreased the number of apoptotic nuclei and nitrotyrosine residues. NOX prevents LPS-induced gut barrier failure by scavenging NO and its toxic derivative, peroxynitrite.
Dickinson
E
E
Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Tuncer
R
R
Nadler
E
E
Boyle
P
P
Alber
S
S
Watkins
S
S
Ford
H
H
D000818:Animals; D016470:Bacteremia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004755:Enterobacteriaceae; D020895:Enterocytes / Q000737:chemistry / Q000201:enzymology / Q000382:microbiology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015918:Infusion Pumps, Implantable; D007408:Intestinal Absorption; D007422:Intestines / Q000166:cytology / Q000201:enzymology / Q000382:microbiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; C116422:NOX 101; D009566:Nitrates; D009942:Organometallic Compounds; D013859:Thiocarbamates; C039642:peroxynitric acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat