ANTIBODIES AGAINST MAC-1 ATTENUATE NEUTROPHIL ACCUMULATION AFTER TRAUMATIC BRAIN INJURY IN RATS

Neutrophils (PMN) accumulate and are associated with cerebrovascular d isturbances after experimental traumatic or ischemic brain injury, and meningitis. We hypothesized that posttraumatic PMN accumulation in br ain is mediated by the PMN adhesion receptor Mac-1 (CD11b/CD18). Anest hetized rats were randomized to receive 2 mg/kg intravenously of murin e monoclonal antibody to rat Mac-1 (1-B6) or anti-Mac-1 F(ab)2' [1-B6F (ab)2'] fragment (Repligen Corp., Cambridge, MA), Control rats were tr eated with isotype matched control antibody. Rats were subjected to pe rcussive trauma to the right parietal cortex 30 min after treatment. R ats were killed 24 h posttrauma, and PMN accumulation was assessed by myeloperoxidase (MPO) activity. The presence of 1-B6F(ab)2' bound to P MN in brain after trauma was assessed by immunohistochemistry. Complet e blood cell counts were obtained before treatment and 24 h after trau ma, Brain MPO activity was reduced by 43% in the 1-B6-treated rats vs. controls (0.31 +/- 0.09 vs 0.55 +/- 0.10 U/g, n = 6/group, p = 0.013) and by 34% in the 1-B6F(ab)2'-treated rats vs. controls (0.43 +/- 0.1 0 vs, 0.65 +/- 0.09 U/g, n = 6/group, p = 0.006). Systemic neutropenia developed in the 1-B6-treated rats (absolute PMN count decreased by 7 3% vs. baseline) but not in rats treated with 1-B6F(ab)2' (absolute PM N count increased by 26 and 25% vs. baseline in treated and controls, respectively). Immunohistochemical staining showed 1-B6F(ab)2' on the surface of infiltrated PMN 24 h after trauma. Mac-1 mediates posttraum atic PMN accumulation in brain, This accumulation can be attenuated by 34%, without reducing circulating PMN, using an anti-Mac-1 F(ab)2' fr agment; however, some PMN coated with 1-B6F(ab)2' still infiltrate int o traumatized tissue, These results are similar to those reported in m odels of cerebral ischemia, and suggest the participation of multiple PMN adhesion pathways after ischemic and traumatic brain injury.