PR-39, a proline/arginine-rich antimicrobial peptide, prevents postischemic microvascular dysfunction

We and others have previously demonstrated that intestinal ischemia-reperfu sion (I/R) is associated with a large increase in oxidant production that c ontributes to microvascular barrier disruption in the small bowel. It has b een suggested that the bulk of tissue damage during reperfusion can be attr ibuted to adherent, activated neutrophils. From these observations, we hypo thesized that pretreatment with PR-39, an endogenous neutrophil antibacteri al peptide that is also a potent inhibitor of the neutrophil NADPH oxidase, would prevent postischemic oxidant production and the development of oxida nt-dependent sequelae to YR such as increased venular protein leakage. To t est this postulate, oxidant production, venular protein leakage, leukocyte adhesion, and leukocyte emigration were monitored during reperfusion in con trol (no ischemia) rat mesenteric venules and in mesenteric venules subject ed to I/R alone or PR-39 + I/R. Treatment with a single intravenous bolus i njection of PR-39 (administered at a dose to achieve an initial blood conce ntration of 5 mu M) abolished I/R-induced leukocyte adhesion and emigration in vivo. In vitro studies indicated that PR-39 prevents platelet-activatin g 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-s timulated neutrophil adhesion to activated endothelial monolayers. In vivo, I/R was associated with a marked and progressive increase in oxidant produ ction and venular protein leakage during reperfusion, effects that were abo lished by PR-39 treatment. The results of this study indicate that PR-39 co mpletely abolishes postischemic leukocyte adhesion and emigration. The time course for inhibition of oxidant production by PR-39 suggests that its ant iadhesive properties account for this effect of the peptide. PR-39 may thus be therapeutically useful for prevention of neutrophil adhesion and activa tion during the postischemic inflammatory response.