Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthase.

摘要: Peroxynitrite, a cytotoxic oxidant formed from nitric oxide (NO) and superoxide, induces DNA strand breakage, which activates the nuclear enzyme poly(ADP-ribose) synthase (PARS; EC 2.4.2.30). The cellular function of PARS was determined in fibroblast lines knockout animals (PARS−/−) corresponding wild-type (PARS+/+), with aid lipophilic inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP). We investigated role peroxynitrite-induced injury vitro also development arthritis vivo. Exposure embryonic fibroblasts PARS+/+ to peroxynitrite caused single-stand breakage activation an acute suppression mitochondrial respiration. INH2BP protected cells against respiration response (50–100 μM). Similarly inhibition INH2BP, PARS−/− were injury. protection by phenotype or waned when challenged higher concentrations oxidant. Inhibition reduced inducible nitric-oxide (iNOS; 1.14.13.39) mRNA levels inhibited production NO immunostimulated cells. had no scavenging hydroxyl radical effects, it exerted additional (nonspecific) effects In collagen-induced arthritis, significant staining for nitrotyrosine, marker formation, found inflamed joints. Oral treatment (0.5 g/kg, daily), starting at onset (day 25), delayed clinical signs days 26–35 improved histological status knee paw. Our data demonstrate that deletion genetic manipulation pharmacological protects oxidant-induced exhibits anti-inflammatory