COMPLEMENT AND TUMOR-NECROSIS-FACTOR-ALPHA CONTRIBUTE TO MAC-1 (CD11BCD18) UP-REGULATION AND SYSTEMIC NEUTROPHIL ACTIVATION DURING ENDOTOXEMIA IN-VIVO/

The increased expression of Mac-1 (CD11b/CD18) adhesion glycoproteins on neutrophils was studied using flow cytometry in male Fischer 344 ra ts treated with 5 mg/kg Salmonella enteritidis endotoxin. A rapid and sustained threefold increase of Mac-1 expression was observed after en dotoxin injection. Inhibition of complement activation with the solubl e complement receptor type 1 (sCR1) completely suppressed the initial up-regulation of Mac-1 (less than or equal to 15 min) but did not prev ent the activation during the later phase (30-90 min). During that tim e period, Mac-1 expression increased in parallel with the concentratio n of tumor necrosis factor alpha (TNF-alpha) in plasma and could be si gnificantly attenuated with TNF antiserum. To verify the results, isol ated human neutrophils were incubated with rat plasma obtained at vari ous times after endotoxin injection. Using shape change as indicator o f neutrophil activation, complement and TNF-alpha could be identified as responsible mediators for neutrophil activation during endotoxemia in vivo. In contrast, the massive neutrophil accumulation in the liver after endotoxin was only slightly reduced by sCR1 and unaffected by T NF antiserum. It is concluded that Mac-1. up-regulation on neutrophils after endotoxin injection in vivo may have limited relevance for hepa tic neutrophil infiltration but may be important for the pathogenesis of endotoxin-induced liver injury by facilitating adherence-dependent neutrophil cytotoxicity.