title: Tumor necrosis factor-alpha antibody eluting stents reduce vascular smooth muscle cell proliferation in saphenous vein organ culture.
abstract: Expression of TNF-alpha a vascular smooth muscle cell (VSMC) mitogen, is up-regulated in injured/proliferating vessel wall. Coronary stents are tested worldwide for their use as local drug delivery devices to address vascular pathophysiology. In this study we have investigated the effect of TNF-alpha antibody eluting stents on VSMC proliferation in human saphenous vein (HSV) organ culture. The adsorption and elution characteristics of TNF-alpha antibody was assessed using stent wires. The stents adsorbed up to 0.25 microg of TNF-alpha antibody/mg of stent and showed a biexponential elution curve, with 34.4% (SD 4.4%) antibody remaining on the stent after 72 h of washing in a perfusion circuit. TNF-alpha antibody delivery from loaded stents to the vessel wall was assessed ex vivo. TNF-alpha and proliferating cell nuclear antigen (PCNA) expression in the vascular specimens was assessed by immunostaining or ELISAs. TNF-alpha ELISAs showed a significant increase in the cytokine levels from the vascular lysates prepared from proliferating tissue culture compared with fresh vein (P < 0.05). Immunohistochemical localization showed an increase in the PCNA positivity of VSMC from these cultures. PCNA staining was barely detected from the fresh tissue. However, a decrease in PCNA staining was observed from tissue sections of venous segments cultured with TNF-alpha antibody eluting stents. PCNA ELISAs demonstrated a 23.7% decline in the antigen levels from the day 7 tissue cultured with such loaded stents. In conclusion, activated VSMC in tissue culture showed an up-regulation of TNF-alpha cytokine, in association with an increase in the PCNA expression in the vessel wall. The local neutralization of this cytokine with TNF-alpha antibody eluting stents reduced VSMC proliferation in the wall. We suggest that TNF-alpha antibody eluting stents may limit restenosis in vivo, which may have important clinical benefits.
authors.affiliation: Division of Cardiology, Clinical Sciences Wing, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, United Kingdom.
authors.forename: Qamar
authors.initials: Q
authors.lastname: Javed
authors.forename: Neil
authors.initials: N
authors.lastname: Swanson
authors.forename: Hunaid
authors.initials: H
authors.lastname: Vohra
authors.forename: Herbert
authors.initials: H
authors.lastname: Thurston
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Gershlick
mesh_terms: D000199:Actins / Q000378:metabolism; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology*; D002455:Cell Division; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D009924:Organ Culture Techniques; D010477:Perfusion; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000378:metabolism; D012501:Saphenous Vein / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D015607:Stents; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology*; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism; D017540:Tunica Media / Q000166:cytology / Q000378:metabolism
chemical_list: D000199:Actins; D000906:Antibodies; D018809:Proliferating Cell Nuclear Antigen; D014409:Tumor Necrosis Factor-alpha