Searching for novel molecular targets of chronic rejection in an orthotopic experimental lung transplantation model.
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.
Research Unit, Experimental Surgery, Hospital Dr Negrín, Las Palmas de Gran Canaria, Spain. norbesr@terra.es
Norberto
N
Santana-Rodríguez
Ricardo
R
García-Herrera
Bernardino
B
Clavo
Pedro
P
Llontop
Miguel A
MA
Ponce-González
Jesús
J
Villar
Ana
A
López-García
María D
MD
Fiuza
Juan C
JC
Rodríguez-Bermejo
José M
JM
García-Castellano
Rubén P
RP
Machín
José A
JA
Ruíz-Caballero
Yanira
Y
Brito
Leandro
L
Fernández-Pérez
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006084:Graft Rejection / Q000235:genetics*; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley
D005819:Genetic Markers; D012333:RNA, Messenger