An investigation of the influence of interleukin-1 on the arterial response to experimental injury
Interleukin-1 (IL-1) is involved in the pathogenesis of coronary artery disease (CAD) and restenosis. IL-1 receptor antagonist (IL-1ra) blocks IL-1 signalling by competitive binding to the Type 1 IL-1 receptor. IL-1ra has been used successfully to modulate inflammatory diseases but its effect on coronary artery injury or restenosis is unknown. An alternative therapeutic target for inhibition of IL-1 is the human soluble type II IL-1 receptor. However, assessment of its binding capacity for porcine IL-1 using surface plasmon resonance technology determined that the human type II IL-1R could not bind porcine IL-1, thereby preventing its use in this work. This work therefore aimed to examine the effect of IL-1ra on the porcine coronary response to injury. Initial pharmacokinetic studies in pig skin determined the inhibitory plasma level of IL-1ra; an intravenous bolus of 0.5mg/kg followed by a 14-day continuous subcutaneous infusion of 2mg/kg/24h. Five groups of animals were studied, all being randomised to either IL-1ra or vehicle according to the above protocol. Group 1: 12 pigs underwent oversized (1.25:1) angioplasty of 2 coronary vessels. Analysis was at 28 days. Groups 2, 3, 4 and 5 underwent coronary stenting (1.25: 1). Group 3 was analysed at 14 days, Groups 2 and 4 at 28 days and Group 5 at 90 days. Histomorphometric measurements were made. A further group of animals were studied in which the IL-1ra was infused for 14 days and analysis was at 17 days in order to determine vessel wall levels of IL-1 by real time PCR.