NEUTROPHIL ACCUMULATION AND PLASMA LEAKAGE INDUCED INVIVO BY NEUTROPHIL-ACTIVATING PEPTIDE-1

Neutorphil accumulation and plasma leakage induced in rabbit skin by neutrophil-activating peptide-1 (NAP-1, a 72 amino acid peptide produced by monocytes and a variety of tissue cells), E. coli endotoxin, and interleukin-1 (IL-1) were compared. Neutrophil accumulation at sites injected with NAP-1 was intense, rapid, and long-lasting; it reached a maximum rate during the first 30 min, continued at constant rate for 4-6 h, and remained detectable up to at least 8 h. In contrast, the neutrophil-attracting effect of endotoxin and IL-1 was slower in onset and more transient; it peaked in the first 2 h and declined to a very low level after 4 h. Plasma leakage induced by NAP-1 had a shorter time course than neutrophil accumulation and ceased after 6 h. Depletion of blood neutrophils by treatment with hydroxyurea prevented the plasma leakage induced by NAP-1 or endotoxin but not by histamine. Desensitization to NAP-1 was studied by restimulation of lesions. Following restimulation with NAP-1 after intervals from 6-10 h, there was diminished infiltration of neutrophils, while nearly normal responses were obtained after an interval of 24 h. Desensitization was dose dependent and affected both plasma leakage and neutrophil accumulation. In lesions initiated with NAP-1 there were normal responses following restimulation with endotoxin but marked desensitization to IL-1, suggesting that NAP-1 may contribute to inflammation induced by IL-1 but not by endotoxin. This study indicates that NAP-1 is a potent mediator of neutrophil accumulation in vivo, with characteristics similar to those reported for C5 fragments, but with a more protracted action.