Inhibition of poly (ADP-nbose) synthetase ameliorates neutrophil recruitment in vivo

Csaba Szabo

    Research output: Contribution to journalArticle

    Abstract

    Introduction: In vitro studies have demonstrated that (he oxidative injury in various cell types is, in pan, related to activation of the nuclear enzyme poly (ADPnbose) syniheuse (PARS). Here we investigated whether inhibition of PARS affects neutrophil recruitment during inflammation. We utilized 3-aminobenzamide, an inhibitor of PARS, and 3-aminobenzoic acid, an ineffective structural analogue. Methods: Male Swiss Albino mice were used for the investigations of the effect of 3-aminobenzamide in the zymosan peritonitis model and leukocyte-endothelium interaction by intravital microscopy. Peritonitis was induced by intrapenlooeal injection of zymosan (12.5 mg/kg). At 2 or 4 h, animals were euthanized and peritoneal cavities washed and differential counting performed. For the measurement of PMN adhesion and emigration in mice treated with 3-aminobenzamide, animals were injected i.p. with 12.5 mg/kg zymosan. Four h later mice were anesthetized and the mesenteric vncuiar bed was exteriorized. The preparation was then mounted on an intravital videornicrotcope system and in post-capillary venules adhesion and leukocyte emigration were monitored. Results: Zymosan injection into murine peritoneal cavities produced a timedependent PMN accumulation. 3-aminobenzamide ( 10-20 mg/kg) resulted in a significant reduction of PMN accumulation, whereas 3-aminobenzoic acid was without significant effects. In the intravital microscopy experiments, zymosan injection induced high numbers of adherent and emigrated leukocytes in mouse mesenteric post-capillary venules 4 h post-administration. Treatment of mice with 3-aminobenzamide (20 mg/kg) immediately before zymosan did not modify the extent of cell adhesion, but reduced the number of cell emigrated outside the post-capillary venules. While roost of (he adherent cells emigrated through the endothelium of the post-capillary venules in the vehicletreated animals, a large majority detached from the endothelial surface following treatment with the PARS inhibitor, the net result being a diminished cell emigration across post-capillary venules, and reduced PMN tissue infiltration. Conclusions: Inhibition of PARS reduces PMN recruitment into inflammatory tissue sites. Extravasated PMNs become activated in the inflammatory sites to secrete a variety of substances such as chemokines and cytokines, complement components. proteases, and reactive nitrogen and oxygen metabolites, which are important mediators of tissue injury. Prevention of neutrophil-dependent inflammatory pathways is likely to contribute to the protective effects of PARS inhibitors in shock and inflammation.

    Original languageEnglish (US)
    Pages (from-to)A77
    JournalCritical care medicine
    Volume26
    Issue number1 SUPPL.
    StatePublished - Dec 1 1998

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    ASJC Scopus subject areas

    • Critical Care and Intensive Care Medicine

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