Pharmacological inhibition, or genetic ablation of poly (ADPribose) synthetase exerts anti-inflammatory effects in a zymosan induced model of multiple organ failure

Csaba Szabo

    Research output: Contribution to journalArticle

    Abstract

    Introduction: In vitro studies have demonstrated that the oxidaove injury in various cell types is, in pan, related to DNA single strand breakage, and consequent activation of the nuclear enzyme poly (ADP-ribose) synrhelase (PARS). Massive ADPnbosylation of nuclear proteins by PARS then results in cellular energy depletion and injury. Here we elucidated whether inhibition of PARS exerts anti-inflammatory effects in a zymosan-induced model of systemic inflammation. We utilized a genetically engineered strain of animals lacking PARS, as well as 3-aminobenzamide. a prototypical pharmacological inhibitor of PARS. Methods: Rats or mice were injected with 500 mg/kg zymosan i.p to induce multiple organ failure. At 18 h after zymosan injection, animals were sacrificed. The abdomen was carefully opened and the peritoneal cavity washed with 2 ml of saline solution with heparin and indomethacin. Lavage fluids were then collected and measured. Lung, liver and small intestinal MPO activities were determined and tissues were also examined histopathologically. The above experiments were performed in rats and mice. in rats, responses in vehicle-preireaied animals and responses in animals pretreated with 3-aminobenzamide ( 10 mg/kg, 10 min prior to zymosan and every 6 h thereafter) were compared. In mice, responses in PARS- and PARS'animals were compared. Results: Injection of zymosan induced non-septic shock and multiple organ failure, with intensive PMN migration into various organs. At 18 h time-point and we observed strong peritoneal inflammation (detected as exudation and leukocyte accumulation) and increased PMN infiltration into various organs. In the wild-type (PARS') control mice, zymosan injection increased serum AST and LDH levels. Treatment of rats with 3anunobenzamide (10 mg/kg) or the absence of PARS in mice resulted in a pronounced reduction of exudate volumes, leukocyte counts in the peritoneum, and significantly attenuated the zymosan-induced increase in the MPO activity in the organs and ameliorated the increase in serum AST and LDH. There was also a marked réduction in the degree of histological injury in the PARS'' mice after zymosan injection, when compared to PARSWmice. The extent of mononuclear cell infiltration and the degree of the histological damage was markedly reduced in the tissues of the PARS'mice. Conclusions: The current data, coupled with a number of recent observations suggest that PARS activation plays a role in the oxidant injury in various forms of inflammation and reperfusion injury. We propose that inhibition of PARS represents a novel strategy for anti-inflammatory therapy.

    Original languageEnglish (US)
    Pages (from-to)A76
    JournalCritical care medicine
    Volume26
    Issue number1 SUPPL.
    StatePublished - Dec 1 1998

    ASJC Scopus subject areas

    • Critical Care and Intensive Care Medicine

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