Department of Cardiology, Giessen University, Germany.
J Cardiovasc Pharmacol. 2010 Feb;55(2):213-8. doi: 10.1097/FJC.0b013e3181ce97f6.
Restenosis after balloon angioplasty or stent placement is characterized by local accumulation of mainly vascular smooth muscle cells and the synthesis of extracellular matrix molecules (ECM).We hypothesized that inhibition of ECM synthesis represents a strategy to prevent trauma-induced neointima formation. Rats were treated with pirfenidone (1 g/kg of body weight orally.), an inhibitor of growth factor-induced collagen synthesis, and subjected to balloon denudation of the carotid artery. Two weeks later, computer-aided morphometry was done and compared with untreated controls (each n = 6). Neointimal proliferative activity was quantified immunohistochemically by counting PCNA-positive nuclei, and collagen deposition was visualized by picrosirius red staining and semi-quantified by Northern blot. Control-injured animals developed marked neointimal thickening within 2 weeks (I/M, mean intima to media ratio: 2.42 +/- 0.15) resulting in an 89.2% luminal narrowing. The neointima mainly consisted of vascular smooth muscle cells embedded in collagen. Neointima formation was strongly reduced when balloon-injured animals had been treated with pirfenidone (I/M ratio 0.22 +/- 0.08, P < 0.001), resulting in a minimal residual narrowing of the lumen (7.9%). I/M ratio did not further increase even after discontinuation of the drug for 14 days (0.35 +/- 0.13). Proliferative activity within the neointima was unaffected by the drug, 4.4% versus 4.8% of neointimal cells stained positive for PCNA in carotid arteries of treated versus untreated animals, respectively. However, picrosirius red staining demonstrated marked attenuation of collagen deposition, a finding that was further confirmed by Northern blot of homogenized vessels. Pirfenidone, currently being investigated clinically for the treatment of various fibrotic diseases, is able to prevent neointimal lesion formation most likely through inhibition of local ECM deposition. Targeting matrix deposition may have an intriguing potential for the prevention of vascular proliferative diseases.
球囊血管成形术或支架置入后的再狭窄的特征是主要的血管平滑肌细胞的局部积累和细胞外基质分子（ECM）的合成。我们假设 ECM 合成的抑制代表了一种预防创伤性新生内膜形成的策略。将吡非尼酮（1 g/kg 体重口服），一种生长因子诱导的胶原合成抑制剂，用于大鼠颈动脉球囊去内皮化。2 周后，进行计算机辅助形态计量学，并与未处理的对照组进行比较（每组 n = 6）。通过计数 PCNA 阳性核来定量免疫组织化学检测新生内膜增殖活性，并通过苦味酸红染色观察胶原沉积，并通过 Northern blot 进行半定量。对照损伤动物在 2 周内发展出明显的新生内膜增厚（I/M，内膜与中膜比：2.42 +/- 0.15），导致管腔狭窄 89.2%。新生内膜主要由嵌入胶原中的血管平滑肌细胞组成。当球囊损伤动物用吡非尼酮治疗时，新生内膜形成明显减少（I/M 比 0.22 +/- 0.08，P < 0.001），导致管腔最小残留狭窄（7.9%）。即使在停药 14 天后，I/M 比值也没有进一步增加（0.35 +/- 0.13）。药物对新生内膜内的增殖活性没有影响，用药物处理和未处理动物的颈动脉中，分别有 4.4%和 4.8%的新生内膜细胞染色 PCNA 阳性。然而，苦味酸红染色显示胶原沉积明显减弱，这一发现通过对匀浆血管的 Northern blot 进一步证实。吡非尼酮目前正在临床研究用于治疗各种纤维化疾病，它能够预防新生内膜病变的形成，很可能是通过抑制局部 ECM 沉积。靶向基质沉积可能为预防血管增殖性疾病提供了一个有趣的潜力。
