TNFα increases the inflammatory response to vascular balloon injury without accelerating neointimal formation

There is now clear evidence for a contributory role of inflammatory processes to restenosis following vascular balloon injury and stent implantation. The aim of the present study was to study the effects of TNFα, administered locally in vivo immediately following balloon angioplasty, on the leukocyte adhesive response and extent of neointimal formation in a rabbit model of subclavian artery injury. Initial in vitro studies were performed with normal isolated artery rings to assess the vascular adhesive response to TNFα or IL-1β. Pre-incubation with either cytokine prior to addition of 51Cr-labelled leukocytes enhanced the adhesion of leukocytes to the artery in both a time- and concentration-dependent manner. Although both cytokines induced an increase in the expression of the adhesion molecules ICAM-1 and VCAM-1, only antibodies to ICAM-1 blocked the enhanced adhesion induced by the cytokines. In artery segments retrieved from rabbits that had previously undergone subclavian artery angioplasty either 24 h or 8 days previously, there was an injury-induced increase in adhesion of leukocytes assessed ex vivo. In segments obtained from rabbits that received a 15 min local infusion of TNFα (2 ng/min) to the injured artery immediately after the angioplasty procedure, leukocyte adhesion assessed ex vivo was further significantly enhanced. The pro-adhesive effect of TNFα was associated with an increased expression of both ICAM-1 and VCAM-1. However, TNFα administration did not alter the extent of neointimal formation observed 8 days after injury. These findings suggest that while TNFα may play a role following vascular injury, it does not act alone to induce neointimal formation. Thus anti-inflammatory strategies targeted at multiple cytokines may be more appropriate than targeting a single cytokine to reduce the response to vascular injury.