INHIBITION OF EXPERIMENTAL VASOSPASM WITH ANTI-INTRACELLULAR ADHESIONMOLECULE-1 MONOCLONAL-ANTIBODY IN RATS

Background and Purpose Inflammation may play a role in delayed chronic vasospasm after aneurysmal subarachnoid hemorrhage. We investigated t he role of intercellular adhesion molecule-1 (ICAM-1) and macrophage/g ranulocyte infiltration in the rat femoral artery model of vasospasm u sing systemic administration of a murine anti-ICAM-1 monoclonal antibo dy (MAb). Methods The femoral arteries (n=72) in Sprague-Dawley rats ( n=36) were enclosed in latex pouches bilaterally. Autologous blood was injected into the pouch on one side, and saline was injected on the c ontralateral side. Chronic vessel narrowing was evaluated with the use of 29 rats, which were randomized into one of three groups for intrap eritoneal injections: (1) anti-ICAM-1 MAb (2 mg/kg per dose, n=10), (2 ) isotype-matched MAb (2 mg/kg per dose, n=9), or (3) saline (n=10), g iven at 3 hours and 3, 6, and 9 days after blood exposure. These rats were killed 12 days after blood exposure, and femoral artery lumen cro ss-sectional areas were determined by computerized image analysis. Sat uration of ICAM-1 binding sites with this dosing schedule was evaluate d by fluorescence-activated cell sorter (FACS) analysis of splenocytes . Immunohistochemical studies with objective cell counts were performe d to evaluate macrophage/granulocyte infiltration at 24 hours in 7 rat s, comparing anti-ICAM-1 MAb treatment (n=4) with isotype-matched cont rol MAb (n=3). Results Animals treated with anti-ICAM-1 MAb showed a s ignificant inhibition of arterial narrowing at 12 days (P=.0081), with lumen patency of 96.5+/-5.3% (mean+/-SEM), compared with 77.3+/-5.6% for isotype-matched MAb and 72.2+/-5.3% for saline-treated controls. F ACS analysis of splenocytes from animals treated with anti-ICAM-1 MAb confirmed saturation of ICAM-1 binding sites. Vessels treated with ant i-ICAM-1 MAb showed a significant decrease in inflammatory cell infilt rates, with objective macrophage/granulocyte counts of 31.3+/-26.6 (me an+/-SEM) per high-powered field, compared with 171.4+/-30.7 for isoty pe-matched control MAb (P=.0027). Conclusions Anti-ICAM-1 MAb administ ered systemically starting 3 hours after blood exposure results in sig nificant inhibition of chronic vasospasm in the rat femoral artery mod el and is correlated with a reduction in the number of infiltrating ma crophages and granulocytes in the periadventitial region of blood-expo sed arteries. We conclude that inflammatory changes associated with IC AM-1-mediated macrophage and granulocyte migration play an important r ole in the development of posthemorrhagic chronic vasospasm in this mo del.