Pirfenidone inhibits early myointimal proliferation but has no effect on late lesion size in rats.
OBJECTIVE
intimal hyperplasia is mediated by smooth muscle cell proliferation, migration and deposition of extracellular matrix. The anti-fibrotic agent pirfenidone has been shown to inhibit pro-fibrotic growth factors in non-vascular inflammatory models. This study investigated the effect of the novel anti-fibrotic agent pirfenidone on the development of neointima.


METHODS
male Sprague-Dawley rats received either standard diet or diet supplemented with pirfenidone (250, 500, 1000 mg/kg/day). Animals underwent left common carotid balloon angioplasty and were explanted at 4, 8, 14 and 28 days and analysed for intimal thickening, pro-fibrotic gene expression, extracellular matrix deposition and metalloproteinase activity.


RESULTS
neointimal thickness was significantly reduced in a dose-dependent manner at 14 days; pirfenidone 250 mg/kg (p<0.005), pirfenidone 500 mg/kg (p<0.001), pirfenidone 1 g/kg ( p<0.001). There were no significant differences in intimal thickening at 28 days. Expression of MMP-2, MMP-9, TIMP-1, collagen III and TGF-beta were all significantly inhibited at 14 days. Both collagen III expression and ECM deposition were reduced at 28 days ( p<0.05 and <0.002 respectively).


CONCLUSIONS
pirfenidone reduces expression of MMPs governing smooth muscle cell proliferation and migration (MMP-2 and 9), and genes favouring ECM accumulation (TIMP-1 and collagen III). This study shows that inhibition of MMP activity is not sufficient to inhibit late lesion size.
Waller
J R
JR
Division of Transplant Surgery, University of Leicester, Leicester, UK.
Murphy
G J
GJ
Bicknell
G R
GR
Sandford
R
R
Margolin
S B
SB
Nicholson
M L
ML
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects* / Q000254:growth & development*; D020212:Carotid Artery Injuries / Q000209:etiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects* / Q000254:growth & development* / Q000293:injuries
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; C093844:pirfenidone; D008666:Metalloendopeptidases