Oxidative stress and apoptosis in a pig model of brain death (BD) and living donation (LD)

Abstract

BackgroundAs organ shortage is increasing, the acceptance of marginal donors increases, which might result in poor organ function and patient survival. Mostly, organ damage is caused during brain death (BD), cold ischemic time (CIT) or after reperfusion due to oxidative stress or the induction of apoptosis. The aim of this study was to study a panel of genes involved in oxidative stress and apoptosis and compare these findings with immunohistochemistry from a BD and living donation (LD) pig model and after cold ischemia time (CIT).MethodsBD was induced in pigs; after 12 h organ retrieval was performed; heart, liver and kidney tissue specimens were collected in the BD (n = 6) and in a LD model (n = 6). PCR analysis for NFKB1, GSS, SOD2, PPAR-alpha, OXSR1, BAX, BCL2L1, and HSP 70.2 was performed and immunohistochemistry used to show apoptosis and nitrosative stress induced cell damage.ResultsIn heart tissue of BD BAX, BCL2L1 and HSP 70.2 increased significantly after CIT. Only SOD2 was over-expressed after CIT in BD liver tissue. In kidney tissue, BCL2L1, NFKB, OXSR1, SOD2 and HSP 70.2 expression was significantly elevated in LD. Immunohistochemistry showed a significant increase in activated Caspase 3 and nitrotyrosine positive cells after CIT in BD in liver and in kidney tissue but not in heart tissue.ConclusionThe up-regulation of protective and apoptotic genes seems to be divergent in the different organs in the BD and LD setting; however, immunohistochemistry revealed more apoptotic and nitrotyrosine positive cells in the BD setting in liver and kidney tissue whereas in heart tissue both BD and LD showed an increase.

The effects of brain death and ischemia on tolerance induction are organ-specific

“…Little change in RNA levels of cytokine gene expression was observed in kidney tissue but substantial increases in RNA for IL-1 and IL-6 were observed in lung and heart tissue after brain death. These organ-specific differences in gene expression following brain death are consistent with previous reports in the literature 18,19 These findings suggest that the differential effects observed after brain death observed in our study result from organ-specific differences in the upregulation of proinflammatory genes like IL-6…”

Exendin‐4 attenuates brain death–induced liver damage in the rat

“…8,25 In order to confirm those findings and test the effects of Ex-4 administration in our experimental system, both direct and indirect evidence of hepatic impairment were investigated. Plasma levels of AST, ALT, and LDH are largely used as indicators of general liver cell dysfunction.…”

Transplantation and Damage-Associated Molecular Patterns (DAMPs)

“…A decade ago, early experiments on a rat model revealed a strong influence of BD condition on chronic graft dysfunction . Emerging evidence now indicates that donor BD conditions, associated with oxidative stress (including oxidative stress‐induced endoplasmic reticulum [ER] stress associated with apoptosis) activate the innate immune system, which leads to development of an acute systemic auto‐inflammatory syndrome , often associated with the demonstration of an apoptotic signature in cells of removed donor organs (kidney, heart) .…”