The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/10/1041/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 7, October 6, 1997 1041-1049

Articles

Inhibition of poly (ADP-ribose) Synthetase Attenuates Neutrophil Recruitment and Exerts Antiinflammatory Effects

Csaba Szabó*, Lina H.K. Lim{ddagger}, Salvatore Cuzzocrea*, Stephen J. Getting{ddagger}, Basilia Zingarelli*, Roderick J. Flower{ddagger}, Andrew L. Salzman*, and Mauro Perretti{ddagger}

From the * Children's Hospital Medical Center, Division of Critical Care, Cincinnati, Ohio 45229; and {ddagger} Department of Biochemical Pharmacology, The William Harvey Research Institute, London EC1M6BQ, United Kingdom

A cytotoxic cycle triggered by DNA single-strand breakage and poly (ADP-ribose) synthetase activation has been shown to contribute to the cellular injury during various forms of oxidant stress in vitro. The aim of this study was to investigate the role of poly (ADP-ribose) synthetase (PARS) in the process of neutrophil recruitment and in development of local and systemic inflammation. In pharmacological studies, PARS was inhibited by 3-aminobenzamide (10–20 mg/kg) in rats and mice. In other sets of studies, inflammatory responses in PARS–/– mice were compared with the responses in corresponding wild-type controls. Inhibition of PARS reduced neutrophil recruitment and reduced the extent of edema in zymosan- and carrageenan-triggered models of local inflammation. Moreover, inhibition of PARS prevented neutrophil recruitment, and reduced organ injury in rodent models of inflammation and multiple organ failure elicited by intraperitoneal injection of zymosan. Inhibition of PARS also reduced the extent of neutrophil emigration across murine mesenteric postcapillary venules. This reduction was due to an increased rate of adherent neutrophil detachment from the endothelium, promoting their reentry into the circulation. Taken together, our results demonstrate that PARS inhibition reduces local and systemic inflammation. Part of the antiinflammatory effects of PARS inhibition is due to reduced neutrophil recruitment, which may be related to maintained endothelial integrity.

Address correspondence to Dr. Csaba Szabó, Children's Hospital Medical Center, Division of Critical Care, 3333 Burnet Avenue, Cincinnati, OH 45229. Phone: 513-636-8714; FAX: 513-636-4892.

1 Abbreviations used in this paper: AST, aspartate aminotransferase; LDH, lactate dehydrogenase; MPO, myeloperoxidase; PARS, poly (ADP-ribose) synthetase.


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