Abstract 4139660: Human IL-8 BAC Transgenic Mice Reveal the Causative Role of IL-8 in Neointima Hyperplasia

Interleukin-8 (IL-8, aka CXCL8) is a chemokine produced by multiple proinflammatory cells. A high level of serum IL-8 is correlated with increased risk of cardiovascular diseases; diseased vessels frequently express high levels of IL-8. Despite these correlations, it remains largely unknown whether IL-8 plays a causative role in vascular disease owing to the lack of mouse ortholog of IL-8 and thus knockout mouse models. To address the knowledge gap, we applied a bacterial artificial chromosome (BAC) transgenic (Tg) mouse model which carries the whole IL-8 gene locus as well as the surrounding regulatory elements to enable the pathophysiological expression of IL-8 in mice. As expected, the expression of IL-8 in the BAC Tg mice is substantially induced by vascular injury and ex vivo culture condition. To determine the role of IL-8 in vascular stenosis, we subjected BAC Tg mice to complete carotid artery ligation injury. We found that neointima formation is significantly increased in BAC Tg mice compared with WT controls; the neointima in Tg mice displays increased accumulation of MAC2 and PCNA positive cells. To further pinpoint the causative role of IL-8 in the phenotype seen in BAC Tg mice, we applied IL-8 antibody to neutralize IL-8 produced in the injured carotid arteries using Pluronic gel immediately after ligation surgery in the BAC Tg mice. We found IL-8 antibody significantly attenuated neointima formation compared with IgG control. Our studies, for the first demonstrated a causative role of IL-8 in neointima formation, suggesting that IL-8 is a potential therapeutic target for vascular stenosis. Our study also indicates BAC IL-8 Tg could serve as a useful tool for investigating the role of IL-8 in various vascular pathologies.