Pentoxifylline pretreatment decreases the pool of circulating activated neutrophils, in-vivo adhesion to endothelium, and improves survival from hemorrhagic shock

Recent research suggests that polymorphonuclear neutrophils (PMNs) play an important role in ischemic organ injury by adhesion to the endothelium and by expression of cytotoxicity via oxygen free radical formation. The number of activated circulating PMNs as measured by the reduction of nitroblue tetrazolium (NBT-positive PMNs) were shown to be closely associated with the trend towards irreversibility in hemorrhagic shock. Our objective was to investigate the effect of pentoxifylline (PTX) on two aspects of the PMN mediated injury: (a) adhesion to the endothelium, and (b) spontaneous circulating PMN activation as a risk factor in a Wiggers type hemorrhagic shock protocol (35 mmHg mean arterial pressure for 90 minutes). The adhesion energy was estimated from the relative rolling velocity of individual PMNs on the endothelium of post-capillary venules in the rat mesentery before and after PTX treatment. The results indicate: (1) that PTX administration leads to a gradual reduction of the adhesion energy in a dose range between 1 to 100 mg/kg, and (2) it was possible to reduce significantly the spontaneous PMN activation in rats pretreated with PTX orally for at least 6 days (40 mg/kg per day). Although there were no significant differences in the PMN count between the PTX and the control group, the number of circulating NBT-positive PMNs before bleeding, as well as during the hypotensive period, was significantly lower in the PTX than in the control group. The 24-hour survival rate after hemorrhagic shock was improved from 50% in the untreated controls to 91% in the PTX group. These results suggest that manipulation of the circulating pool of PMNs by an agent that decreases the number of activated cells and reduces PMN adhesion to the endothelium, can significantly improve survival in this shock model.