在原位实验性肺移植模型中寻找慢性排斥反应的新分子靶标。

Searching for novel molecular targets of chronic rejection in an orthotopic experimental lung transplantation model.

机构信息

Research Unit, Experimental Surgery, Hospital Dr Negrín, Las Palmas de Gran Canaria, Spain.

出版信息

J Heart Lung Transplant. 2012 Feb;31(2):213-21. doi: 10.1016/j.healun.2011.11.011.

DOI:10.1016/j.healun.2011.11.011

PMID:22305384

Abstract

BACKGROUND

Chronic rejection (CR) is the main reason for the limited survival rates among lung transplant (LT) recipients. There remains no effective treatment for CR. The aim of this study was to identify new molecular mechanisms involved in CR by using DNA microarray analysis.

METHODS

We performed 10 left LTs using the microsurgical cuff technique in inbred Sprague-Dawley rats. Lung isograft samples were obtained 3 months after surgery. We analyzed histologic, apoptotic and gene expression changes by DNA microarray and quantitative PCR analysis.

RESULTS

Histologic analyses confirmed signs of CR in all lungs and positive labeling for apoptotic and anti-apoptotic markers. A total of 702 genes were regulated in the CR lungs: 317 genes were upregulated and 385 were downregulated. Significant changes for about 30 biologic processes, including regulation of the cytoskeleton, and 15 signaling pathways, such as adherens junctions, were observed. We found significantly increased mRNA expression of the Cldn5, Epas1, Tgfb1, Vegf, Selp1, Hsp27 and Igf1 genes.

CONCLUSIONS

This is the first experimental study performed in an orthotopic model of LT using DNA microarray analysis. The individual genes, biologic process and pathways identified may represent novel targets that could be manipulated and contribute to the development of treatments capable of providing protection from CR.

摘要

背景

慢性排斥反应（CR）是肺移植（LT）受者生存率有限的主要原因。目前还没有针对 CR 的有效治疗方法。本研究旨在通过 DNA 微阵列分析来确定 CR 涉及的新分子机制。

方法

我们使用微外科袖套技术在近交 Sprague-Dawley 大鼠中进行了 10 例左 LT。手术后 3 个月获得肺移植物样本。我们通过 DNA 微阵列和定量 PCR 分析分析了组织学、凋亡和基因表达变化。

结果

组织学分析证实了所有肺中的 CR 迹象以及凋亡和抗凋亡标志物的阳性标记。CR 肺中共有 702 个基因受到调控：317 个基因上调，385 个基因下调。观察到约 30 个生物过程的显著变化，包括细胞骨架的调节，以及 15 个信号通路，如黏附连接、Epas1、Tgfb1、Vegf、Selp1、Hsp27 和 Igf1 基因的表达显著增加。