Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the rat

Abstract

1 The e ects of the long lasting and potent PAF receptor antagonist UK74505 were assessed on the local and remote injuries following ischaemia and reperfusion (I/R) of the superior mesenteric artery (SMA) in rats.2 In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and neutrophil accumulation, there was signi®cant tissue haemorrhage, blood neutropenia, systemic hypotension and elevated local and systemic TNFa levels. 3 Post-ischaemic treatment with the selectin blocker fucoidin (10 mg kg 71 ) prevented neutrophil accumulation in tissue and, in consequence, all the local and systemic injuries following severe I/R. 4 Treatment with an optimal dose of UK74505 (1 mg kg 71 ) also reversed local and remote neutrophil accumulation, increases in vascular permeability and intestinal haemorrhage. UK74505 partially inhibited blood neutropenia and reperfusion-induced hypotension. 5 Interestingly, both fucoidin and UK74505 prevented the local, but not systemic, increases of TNF-a levels following severe I/R injury, demonstrating an important role of migrating cells for the local production of TNF-a. However, the results do not support a role for PAF as an intermediate molecule in the production of systemic TNF-a. 6 The bene®cial e ects of UK74505 and other PAF receptor antagonists in models of I/R injury in animals and the safety of UK74505 use in man warrant further investigations of the use of this drug as preventive measure for I/R injury in humans.

IL-1-Driven Endogenous IL-10 Production Protects Against the Systemic and Local Acute Inflammatory Response Following Intestinal Reperfusion Injury

“…Following prolonged (120-min) ischemia of the vascular territory irrigated by the superior mesenteric artery, there is a marked local (intestinal), remote (lungs), and systemic inflammatory response characterized by increased vascular permeability, neutropenia, and neutrophil influx into tissues, marked proinflammatory cytokine production, and hypotension (5)(6)(7)(8). These inflammatory events are accompanied by a great degree of lethality, which is remarkably associated with the serum concentration of TNF-␣ (6,9).…”

“…The abdominal incision was occluded with gauze moistened with warm saline. After ischemia, reperfusion was initiated by removal of the occlusion and was maintained for 120 min (5). The temperature of the animals was maintained with a warm blanket, and no fluid was given throughout the observation period.…”

“…Results are presented as the amount of Evans Blue per microgram per 100 mg of tissue. The extent of neutrophil accumulation in the intestine, mesentery, and right lung tissue was measured by assaying myeloperoxidase activity, as previously described (5). Results are expressed as the total number of neutrophils by comparing the OD of tissue supernatant with the OD of rat peritoneal neutrophils processed in the same way as tissue samples.…”

“…The extravasation of Evans Blue dye into the intestine, mesentery, and left lung tissue was used as an index of increased vascular permeability, as previously described (5). Results are presented as the amount of Evans Blue per microgram per 100 mg of tissue.…”

“…Determination of the concentration of hemoglobin in intestinal tissue using Drabkin's color reagent was used as an index of tissue hemorrhage, as previously described (5).…”