title: Pirfenidone inhibits early myointimal proliferation but has no effect on late lesion size in rats.
abstract: 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.
authors.affiliation: Division of Transplant Surgery, University of Leicester, Leicester, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Waller
authors.forename: G J
authors.initials: GJ
authors.lastname: Murphy
authors.forename: G R
authors.initials: GR
authors.lastname: Bicknell
authors.forename: R
authors.initials: R
authors.lastname: Sandford
authors.forename: S B
authors.initials: SB
authors.lastname: Margolin
authors.forename: M L
authors.initials: ML
authors.lastname: Nicholson
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; C093844:pirfenidone; D008666:Metalloendopeptidases