Intragraft gene expression profiles by cDNA microarray in small-for-size liver grafts

Abstract

The aim of this study is to identify the molecular mechanism of small-for-size graft injury through large-scale expression measurement of intragraft gene profile by carrier DNA (cDNA) microarray screening in liver transplantation. The studies compared 1,081 intragraft genes expression profiles using cDNA microarray of small-for-size grafts (<30% of recipient liver weight) with those of whole grafts (control group) 1, 3, and 24 hours after reperfusion in a rat liver transplantation model. Intragraft gene expression was detected by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR). Hepatic ultrastructural features were shown by electron microscopy. In the small-for-size grafts, by cDNA microarray study, the vasoconstriction genes were found up-regulated together with adhesion molecules at 1 hour after reperfusion. Three and 24 hours after reperfusion, the vasopressin genes were found up-regulated together with adhesion molecules, inflammatory mediators and cell death signals, accompanied with down-regulation of the genes related to energy metabolism. By quantitative RT-PCR, intragraft messenger RNA (mRNA) expression of endothelin-1 (ET-1) and endothelin-1 receptor A (ETA) was up-regulated during the first 24 hours after reperfusion accompanied with down-regulation of heme oxygenase-1 (HO-1). The intragraft mRNA and plasma levels of inflammatory cytokines (interleukin [IL]-6, IL-15, tumor necrosis factor [TNF]-α) also were overexpressed during the first 24 hours after reperfusion. Sinusoidal congestion and disruption were found accompanied with mitochondrial swelling during the first 24 hours after reperfusion. The up-regulation of intragraft vasoconstriction genes accompanied by early overexpression of adhesion molecules and apoptotic signals, as well as down-regulation of HO-1 in small-for-size grafts may be related to sinusoidal injury leading to graft damage in liver transplantation.