EFFECT OF 5-AMINOSALICYLIC ACID AND ANALOGOUS SUBSTANCES ON SUPEROXIDE GENERATION AND INTRACELLULAR FREE CALCIUM IN HUMAN NEUTROPHILIC GRANULOCYTES

Activated polymorphonuclear leukocytes (PMNs), which are found in the inflammatory lesions of chronic inflammatory bowel disease, produce ti ssue-destructive oxygen-derived free radicals. The influence of 5-amin osalicylic acid (5-ASA), its acetylated metabolite (Ac-5-ASA), sulfasa lazine (SAZ), and olsalazine (OLZ) (5-ASA dimer linked by an azo group ) in pharmacologically relevant concentrations (0.1-10 mM) were tested on PMN superoxide production with either the receptor-specific agent formyl-methionyl-leucyl-phenylalanine (fMLP) or the protein kinase C a ctivator phorbol myristate acetate (PMA). Inhibition of receptor-speci fic superoxide production occurred at 0.07, 0.32, and 0.63 mM (IC50 va lues) for 5-ASA, SAZ, and OLZ, respectively. No inhibitory effects of SAZ and OLZ were observed when PMA was applied as stimulus for PMN sup eroxide production. The results indicate that the signal to which PMNs respond by generating superoxide is primarily due to calcium release from intracellular stores. They further suggest that SAZ and OLZ may a ffect the oxygen-derived free radical production in human PMNs by unsp ecific cytotoxicity or by interference with the nicotinamide adenine d inucleotide phosphate, reduced (NADPH) oxidase system, whereas 5-ASA i tself is a free radical scavenger.