Iyer S N, Gurujeyalakshmi G, Giri S N
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, USA.
J Pharmacol Exp Ther. 1999 Apr;289(1):211-8.
A time course study was carried out to elucidate the mechanisms for antifibrotic effect of pirfenidone (PD). Hamsters were intratracheally (i.t.) instilled with saline (SA) or bleomycin (BL) (7.5 units/kg/5 ml). The animals were fed a diet containing 0.5% PD or the same control diet (CD) without the drug 2 days before and throughout the study. The animals were sacrificed at various times after instillation. The lung hydroxyproline level in BL + CD groups was gradually increased and peaked at 21 days to 181% of the SA + CD control. The BL + PD-treated groups showed a gradual decrease in their lung collagen content, showing a maximum reduction of 40% at day 21. The lung malondialdehyde levels of the BL + CD groups were increased by several-fold of the corresponding SA + CD groups at various times. The lung prolyl hydroxylase (PH) activities in the BL + CD groups were also increased by several-fold of the corresponding SA + CD groups at these time points. The hamsters in the BL + PD showed a gradual decrease in the lung malondialdehyde levels from 10 to 21days compared with their corresponding BL + CD groups. Treatment with PD also reduced the lung PH activities in the BL + PD groups compared with the corresponding BL + CD groups. However, PD failed to manifest any direct inhibitory effect on PH activity in vitro. BL treatment increased the lung procollagen I and III gene expressions in the BL + CD groups by several-fold at varying times compared with the corresponding SA + CD, and treatment with PD in the BL + PD groups significantly down-regulated the BL-induced overexpression of these genes. Studies evaluating the regulation of these genes at the transcriptional level revealed PD significantly reduced the transcription of PC I at 14 days. Our results indicate that the antifibrotic effect of PD was partly due to suppression of the BL-induced inflammatory events and partly due to down-regulation of BL-induced overexpression of lung procollagen I and III genes.
进行了一项时间进程研究以阐明吡非尼酮（PD）抗纤维化作用的机制。将仓鼠经气管内（i.t.）注入生理盐水（SA）或博来霉素（BL）（7.5单位/千克/5毫升）。在研究前2天及整个研究过程中，给动物喂食含0.5% PD的饮食或不含该药物的相同对照饮食（CD）。在注入后不同时间处死动物。BL + CD组的肺羟脯氨酸水平逐渐升高，在21天时达到峰值，为SA + CD对照组的181%。BL + PD治疗组的肺胶原含量逐渐降低，在第21天时最大降低了40%。在各个时间点，BL + CD组的肺丙二醛水平比相应的SA + CD组增加了几倍。在这些时间点，BL + CD组的肺脯氨酰羟化酶（PH）活性也比相应的SA + CD组增加了几倍。与相应的BL + CD组相比，BL + PD组的仓鼠在10至21天肺丙二醛水平逐渐降低。与相应的BL + CD组相比，PD治疗也降低了BL + PD组的肺PH活性。然而，PD在体外对PH活性未表现出任何直接抑制作用。与相应的SA + CD相比，BL治疗在不同时间使BL + CD组的肺I型和III型前胶原基因表达增加了几倍，而BL + PD组用PD治疗显著下调了BL诱导的这些基因的过表达。在转录水平评估这些基因调控的研究表明，PD在14天时显著降低了PC I的转录。我们的结果表明，PD的抗纤维化作用部分归因于对BL诱导的炎症事件的抑制，部分归因于对BL诱导的肺I型和III型前胶原基因过表达的下调。
