VEROTOXIN INDUCES HEMORRHAGIC LESIONS IN RAT SMALL-INTESTINE - TEMPORAL ALTERATION OF VASOACTIVE SUBSTANCES

E. coli O157:H7 produces a cytotoxin active against Vero cells that ha s been termed verotoxin. In this study, we demonstrated that local int raarterial injection of verotoxin induced a decrease in bloodflow and an increase in hemorrhagic lesions in rat small intestine. Significant increases in the area of hemorrhagic lesions were observed at 120 min after verotoxin injection. These lesions were produced by either vero toxin 1 or 2, but verotoxin 2 produced more extensive lesions. The tem poral alteration of vasoactive substances in microcirculatory beds was determined after the administration of culture filtrate of E. coli O1 57:H7. Tissue-type plasminogen activator activity in regional plasma w as significantly elevated as early as 30 min, suggesting that local fi brinolytic activation mediated by microvascular endothelium occurred T here was also early elevation of platelet-activating factor content in the ileal mucosa and its level remained significantly elevated therea fter Intestinal bloodflow, as determined by a laser Doppler flowmeter, stat-red to decrease at about 45 min. The platelet-activating factor antagonist CV6209 was shown to attenuate the decrease in blood flow as well as the development of hemorrhagic lesions, demonstrating that pl atelet-activating factor is an important mediator for the microcircula tory damage. Accumulation of neutrophils demonstrated by myeloperoxida se activity in the intestinal mucosa and overproduction of oxygen-radi cals from neutrophils of the mesenteric veins determined by the lumino l-dependent chemiluminescence assay were observed at 60 min, correspon ding with the decreased bloodflow. Platelet-activating factor may be c losely involved in the process of leukocyte accumulation and increased oxygen radical generation, because CV6209 also significantly attenuat ed these changes. Verotoxin is considered to induce vascular endotheli al cell damage and elicit the accumulation of neutrophils in intestina l microvascular beds, leading to hemorrhagic lesions via mediators inc luding tissue-type plasminogen activator, platelet-activating factor, and oxygen-derived free radicals.