Immunolocalization and temporal distribution of cytokine expression during the development of vein graft intimal hyperplasia in an experimental model.
OBJECTIVE
Vein graft stenosis caused by intimal hyperplasia (IH) accounts for 30% to 50% of late bypass graft failures; however, the biochemical mediators of vein graft IH have been poorly defined. We attempted to evaluate the spatial and temporal distribution of five principal cytokines (interleukin-1 beta [IL-1 beta], platelet-derived growth factor-AA [PDGF-AA], basic fibroblast growth factor [bFGF], interferon gamma [INF gamma], and tumor necrosis factor alpha [TNF-alpha]) during the development of IH in a rat vein graft model.


METHODS
Rat epigastric vein interposition grafts in the femoral artery were harvested at 6 hours, 2 days, 1 week, 2 weeks, and 4 weeks after the grafting procedure and studied with immunohistochemical and standard histologic techniques. The cytokine expression in the endothelium and media/neointima was quantified as the percentage of immunopositive cells per high-power field.


RESULTS
Maximal hyperplasia occurred 2 weeks after the grafting procedure. Peak expression of IL-1 beta and bFGF occurred by 2 days. PDGF-AA expression paralleled the development of IH, peaking at 2 weeks and then declining. TNF-alpha expression increased at 1 week and remained elevated. INF gamma was seen only in control grafts.


CONCLUSIONS
The coordinated early release of IL-1 beta and bFGF and the down-regulation of INF gamma seem to trigger an inflammatory response, thereby initiating IH. The process then is propagated by the release of PDGF-AA and TNF-alpha, with concomitant smooth muscle cell proliferation and production of extracellular matrix. It is likely that this complex milieu of local paracrine signaling is required to generate the hyperplastic response seen in failing vein grafts.
Faries
P L
PL
Department of Surgery, Montefiore Medical Center, University Hospital for the Albert Einstein College of Medicine, New York, N.Y. 10467, USA.
Marin
M L
ML
Veith
F J
FJ
Ramirez
J A
JA
Suggs
W D
WD
Parsons
R E
RE
Sanchez
L A
LA
Lyon
R T
RT
D000199:Actins / Q000378:metabolism; D000818:Animals; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005263:Femoral Artery / Q000601:surgery; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000378:metabolism*; D006965:Hyperplasia; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology; D014680:Veins / Q000637:transplantation*
D000199:Actins; D016207:Cytokines; D007375:Interleukin-1; D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D014409:Tumor Necrosis Factor-alpha; C075278:platelet-derived growth factor A; D016222:Fibroblast Growth Factor 2; D007371:Interferon-gamma