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001-es BibID:	BIBFORM028456
Első szerző:	Szabó Csaba (orvos)
Cím:	Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthase / Csaba Szabó, László Virág, Salvatore Cuzzocrea, Gwen S. Scott, Paul Hake, Michael P. O'Connor, Basilia Zingarelli, Andrew Salzman, Ernest Kun
Dátum:	1998
ISSN:	0027-8424
Megjegyzések:	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 from PARS knockout animals (PARS-/-) and corresponding wild-type animals (PARS+/+), with the aid of the lipophilic PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP). We investigated the role of PARS in peroxynitrite-induced fibroblast injury in vitro and also in the development of arthritis in vivo. Exposure of embryonic fibroblasts from the PARS+/+ animals to peroxynitrite caused DNA single-stand breakage and PARS activation and caused an acute suppression of mitochondrial respiration. INH2BP protected the PARS+/+ cells against the suppression of mitochondrial respiration in response to peroxynitrite (50-100 microM). Similarly to PARS inhibition with INH2BP, the PARS-/- cells were protected against peroxynitrite-induced injury. The protection against cellular injury by PARS-/- phenotype or INH2BP waned when cells were challenged with higher concentrations of the oxidant. Inhibition of PARS by INH2BP or by PARS-/- phenotype reduced inducible nitric-oxide synthase (iNOS; EC 1.14.13.39) mRNA levels and inhibited production of NO in immunostimulated cells. INH2BP had no peroxynitrite scavenging or hydroxyl radical scavenging effects, and it exerted no additional (nonspecific) effects in the PARS-/- cells. In collagen-induced arthritis, significant staining for nitrotyrosine, a marker of peroxynitrite formation, was found in the inflamed joints. Oral treatment with INH2BP (0.5 g/kg, daily), starting at the onset of arthritis (day 25), delayed the development of the clinical signs at days 26-35 and improved histological status in the knee and paw. Our data demonstrate that deletion of PARS by genetic manipulation or pharmacological inhibition of PARS protects against oxidant-induced cellular injury in vitro and exhibits anti-inflammatory effects in vivo.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban nitric oxide superoxide inflammation DNA single-strand break inducible nitric-oxide synthase külföldön készült közlemény
Megjelenés:	Proceedings of The National Academy Of Sciences of The United States Of America 95 : 7 (1998), p. 3867-3872. -
További szerzők:	Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Cuzzocrea, Salvatore Scott, Gwen S. Hake, Paul O'Connor, Michael Zingarelli, Basilia Salzman, Andrew L. Kun, Ernest
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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