HYPERTONICITY REGULATES THE FUNCTION OF HUMAN NEUTROPHILS BY MODULATING CHEMOATTRACTANT RECEPTOR SIGNALING AND ACTIVATING MITOGEN-ACTIVATEDPROTEIN-KINASE P38

Excessive neutrophil activation causes posttraumatic complications, wh ich may be reduced with hypertonic saline (IIS) resuscitation, We test ed if this is because of modulated neutrophil function by HS. Clinical ly relevant hypertonicity (10-25 mM) suppressed degranulation and supe roxide formation in response to fMLP and blocked the activation of the mitogen activated protein kinases (MAPK) ERK1/2 and p38, but did not affect Ca2+ mobilization. HS did not suppress oxidative burst in respo nse to phorbol myristate acetate (PMA). This indicates that HS suppres ses neutrophil function by intercepting signal pathways upstream of or apart from PKC. HS activated p38 by itself and enhanced degranulation in response to PKC activation. This enhancement was reduced by inhibi tion of p38 with SB203580, suggesting that p38 up-regulation participa tes in NS-induced enhancements of degranulation. HS had similar effect s on the degranulation of cells that were previously stimulated with f MLP, but had no effect on its own, suggesting that HS enhancement of d egranulation requires another signal. We conclude that depending on ot her stimuli, WS can suppress neutrophil activation by intercepting mul tiple receptor signals or augment degranulation by enhancing p38 signa ling. In patients HS resuscitation may reduce posttraumatic complicati ons by preventing neutrophil activation via chemotactic factors releas ed during reperfusion.