Biomedical subjects
Jan IJzermans
Publications and source records attributed to Jan IJzermans.
Living kidney donors and hypoxia-inducible factor-1alpha.
BACKGROUND: Hypoxia inducible factor (HIF)-1, a heterodimeric transcription factor composed of alpha and beta subunits, is induced in the adaptive response to hypoxia and is critical for initiating the transcriptional activation of growth factors. We speculate that prolonged ischemia and hypoxia time leads to the production of HIF-1alpha, which in turn induces the production of fibrogenic cytokines in the graft. METHODS: To investigate our hypothesis, we measured the expression of HIF-1alpha in time-zero biopsy specimens from living-donor kidneys (< or =2.5 hr of ischemia) and cadaveric donor kidneys (12-32 hr of ischemia). RESULTS: By real time reverse-transcriptase polymerase chain reaction analysis, the mRNA expression level of HIF-1alpha was fivefold lower in time-zero biopsy specimens from living-donor kidneys than in specimens from cadaveric donor kidneys. In these time-zero biopsy specimens, the mRNA expression level of the fibrogenic cytokine transforming growth factor-beta was also significantly lower (twofold). CONCLUSIONS: Low HIF-1alpha mRNA expression levels correlate with short ischemia times and prevent the transcription of fibrogenic cytokines that initiate the irreversible process of graft fibrosis.
No functional benefit for hDAF-transgenic rat livers despite protection from tissue damage following perfusion with human serum.
Currently, xenogeneic extracorporeal liver perfusion is used in the treatment of acute liver failure. In order to determine whether transgeneity for human regulatory proteins could improve the functional outcome of the ex-vivo liver in relation to the histopathological changes, we studied the effect of the humoral mechanism in xenogeneic isolated rat liver perfusion in normal and transgenic rat livers. Isolated rat liver perfusion was performed for 2 h in normal rat livers with Krebs Henseleit (KH) and human serum (HS), and in livers transgenic for human decay accelerating factor (hDAF; Tg HS). Function of the liver was established by measurement of liver enzymes and bile production, and clearance of bromosulphophthalein (BSP). Tissue specimens taken after perfusion were analysed by routine histology and immunofluorescence staining for C3c deposition. No change in release of liver enzymes could be established throughout the perfusion period. In the 2nd hour, a higher level of bile production was seen for the transgenic group than for the HS group. The transgenic rat livers outperformed the normal livers perfused with HS, when BSP concentration in the bile was measured; however, clearance of BSP from the perfusate was not significantly different. Haematoxylin-eosin (HE) staining of the liver tissue showed evidence of hyperacute rejection in the HS group. There was only mild tissue injury in the transgenic liver. High-intensity fluorescent staining for C3c deposition was seen in the normal livers perfused with HS, and significantly less in the transgenic livers. Although histologically less tissue damage and less C3c deposition was shown, no significantly improved function of the livers transgenic for hDAF was established. These results suggest that for short-term extracorporeal liver perfusion transgenesis offers no functional benefit.