Abstract

EFFECT OF POLY (ADP-RIBOSE) POLYMERASE INHIBITION ON MORPHO-FUNCTIONAL STATE OF IMMUNOCYTES UNDER THE CONDITION OF EXPERIMENTAL ENDOTOXEMIA IN MICE

Nataliya Grushka*, Svitlana Pavlovych, Olena Kondratska, Nataliya Pilkevich and Roman Yanchii

ABSTRACT

Recent in vivo and in vitro evidence suggest that inhibitors of poly (ADP-ribose) polymerase (PARP)-1 could be promised in the treatment of inflammatory disorders and conditions associated with an inflammatory component. In our work, we used a murine model of lipopolysaccharide (LPS) induced endotoxemia to investigate the effect of PARP-1 inhibitor, 4-hydroxyquinazoline (4-HQN), on morpho-functional state of the cells of innate and adaptive immunity. We have found that the administration of LPS to mice induced an inflammatory process with significant damage to the immune system cells. There was a pronounced genotoxic stress of immunocytes (according to Comet assay), a loss of their viability what was accompanied by an increased cell death by necrosis and apoptosis, as well as a significant increase in functional and metabolic activity of neutrophils (according to the nitroblue tetrazolium (NBT) test and the lysosomal-cationic test (LCT)). Introduction to the endotoxemic mice of 4-HQN exhibited cytoprotective effect on thymus and lymph node cells: reduced DNA damage and cell death, especially necrosis. 4-HQN administration also contributed to the normalization of neutrophil activity. These findings indicate that pro-inflammatory and immunogenic necrotic cell death and an increase of active oxygen form (AOF) generation caused by PARP-1 may be important mechanisms for enhancing LPS-induced immune inflammation. Consequently, our results indicate that PARP-1 is involved in cell damage, in particular immunocytes, during experimental endotoxemia, as well as indicate the promising use of PARP-1 inhibitors as cytoprotectors in the complex prevention and treatment of endotoxin-induced diseases.

Keywords: poly (ADP-ribose) polymerase, lipopolysaccharide, PARP inhibition, neutrophils, cell death, DNA damage.