We and others have previously demonstrated that intestinal
ischemia-reperfusion (I/R) is associated with a large increase in
oxidant production that contributes to microvascular barrier disruption in the small bowel. It has been suggested that the bulk of tissue damage during reperfusion can be attributed to adherent, activated neutrophils. From these observations, we hypothesized that pretreatment with
PR-39, an endogenous neutrophil antibacterial
peptide that is also a potent inhibitor of the neutrophil
NADPH oxidase, would prevent postischemic
oxidant production and the development of
oxidant-dependent sequelae to I/R such as increased venular
protein leakage. To test this postulate,
oxidant production, venular
protein leakage, leukocyte adhesion, and leukocyte emigration were monitored during reperfusion in control (no
ischemia) rat mesenteric venules and in mesenteric venules subjected to I/R alone or
PR-39 + I/R. Treatment with a single intravenous bolus injection of
PR-39 (administered at a dose to achieve an initial blood concentration of 5 microM) abolished I/R-induced leukocyte adhesion and emigration in vivo. In vitro studies indicated that
PR-39 prevents
platelet-activating factor-induced neutrophil chemotaxis as well as
phorbol myristate acetate (PMA)-stimulated
intercellular adhesion molecule-1 expression by cultured endothelial cells.
PR-39 pretreatment of rat neutrophils also blocked PMA-stimulated neutrophil adhesion to activated endothelial monolayers. In vivo, I/R was associated with a marked and progressive increase in
oxidant production and venular
protein leakage during reperfusion, effects that were abolished by
PR-39 treatment. The results of this study indicate that
PR-39 completely abolishes postischemic leukocyte adhesion and emigration. The time course for inhibition of
oxidant production by
PR-39 suggests that its antiadhesive properties account for this effect of the
peptide.
PR-39 may thus be therapeutically useful for prevention of neutrophil adhesion and activation during the postischemic inflammatory response.