Inhibition of experimental vasospasm with anti-intercellular adhesion molecule-1 monoclonal antibody in rats

Background and Purpose: Inflammation may play a role in delayed chronic vasospasm after aneurysmal subarachnoid hemorrhage. We investigated the role of intercellular adhesion molecule-1 (ICAM-1) and macrophage/granulocyte infiltration in the rat femoral artery model of vasospasm using systemic administration of a murine anti-ICAM-1 monoclonal antibody (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 contralateral side. Chronic vessel narrowing was evaluated with the use of 29 rats, which were randomized into one of three groups for intraperitoneal 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), given 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 cross-sectional areas were determined by computerized image analysis. Saturation of ICAM-1 binding sites with this dosing schedule was evaluated by fluorescence-activated cell sorter (FACS) analysis of splenocytes. Immunohistochemical studies with objective cell counts were performed to evaluate macrophage/granulocyte infiltration at 24 hours in 7 rats, comparing anti-ICAM-1 MAb treatment (n=4) with isotype-matched control MAb (n=3). Results: Animals treated with anti-ICAM-1 MAb showed a significant 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. FACS analysis of splenocytes from animals treated with anti-ICAM-1 MAb confirmed saturation of ICAM-1 binding sites. Vessels treated with anti-ICAM-1 MAb showed a significant decrease in inflammatory cell infiltrates, with objective macrophage/granulocyte counts of 31.3±26.6 (mean±SEM) per high-powered field, compared with 171.4±30.7 for isotype-matched control MAb (P=.0027). Conclusions: Anti-ICAM-1 MAb administered systemically starting 3 hours after blood exposure results in significant inhibition of chronic vasospasm in the rat femoral artery model and is correlated with a reduction in the number of infiltrating macrophages and granulocytes in the periadventitial region of blood-exposed arteries. We conclude that inflammatory changes associated with ICAM-1-mediated macrophage and granulocyte migration play an important role in the development of posthemorrhagic chronic vasospasm in this model.