The novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin, prevents local and remote organ injury following intestinal ischemia/reperfusion in rats.
BACKGROUND
Nuclear factor-kappaB regulates the expression of several genes involved in inflammation, the immune response, apoptosis, cell survival, and proliferation. Many of these same genes are activated during ischemia/reperfusion (I/R) injury. Here, we examined the anti-inflammatory efficacy of a newly developed nuclear factor-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in the intestinal I/R injury model of rats.


METHODS
Intestinal ischemia was induced by occluding the superior mesenteric artery for 60 min. The experimental animals were divided into two groups: untreated group, control; treated group, DHMEQ-treated (20 mg/kg). DHMEQ were administered intraperitoneally at 60 min prior to clamping and 5 min prior to reperfusion. Animal survival rates, intestinal tissue blood flow, serum levels of tumor necrosis factor-alpha, and interleukin-6, and the histopathology of both the intestine and the lung were analyzed.


RESULTS
The DHMEQ-treated animals exhibited higher values of intestinal tissue blood flow and suppression of tumor necrosis factor-alpha and interleukin-6 production, resulting in marked prolongation of their survival times. Histopathological findings obtained by examining tissues from control animals revealed severe intestinal mucosal damage and disruption of the lung alveolar architecture accompanied by hemorrhage and marked neutrophilic infiltration. These findings were significantly ameliorated in DHMEQ-treated animals.


CONCLUSIONS
DHMEQ effectively prevented both intestine and lung injuries in rat intestinal I/R models. This agent may possess a good potency for clinical application in various pathological settings including intestinal I/R and/or inflammatory acute lung injury.
Suzuki
Tomomi
T
Department of Surgery, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan.
Yamashita
Kenichiro
K
Jomen
Wataru
W
Ueki
Shinya
S
Aoyagi
Takeshi
T
Fukai
Moto
M
Furukawa
Hiroyuki
H
Umezawa
Kazuo
K
Ozaki
Michitaka
M
Todo
Satoru
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D003512:Cyclohexanones / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007410:Intestinal Diseases / Q000517:prevention & control*; D008171:Lung Diseases / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*
D000893:Anti-Inflammatory Agents; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin