Induction of specific stress response increases resistance of rat liver allografts to cold ischemia and reperfusion injury

Abstract

Heme oxygenase-1 (HO-1) has been shown to increase cellular resistance against oxidative injury, but the functional significance of this is currently obscure. We investigated the protective role of HO-1, induced by tin-protoporphyrin IX (SnPP), in attenuating liver transplantation injury. Lewis rats were intraperitoneally treated with saline as control, 50 pmol/kg of SnPP, or 2 mg/kg of cycloheximide (CHX) before SnPP injection. Gene expression of HO-1 was induced after either treatment with SnPP-or CHX + SnPP instead of saline, whereas HO-1 protein synthesis was enhanced in Kupfferlike dendritic cells of the SnPPtreated group. Following reperfusion of liver grafts preserved for 30 h, there were fewer intercellular adhesion molecule-1 -positive cells in SnPP-treated livers, significantly reduced numbers of dead cells, and enhanced graft viability. The present data suggest that increased synthesis of HO-1 protein by SnPP pre-conditioning is linked to the improved liver graft viability through inhibition of inflammatory adhesion molecules.Keywords Heme oxygenase-1 . Cold ischemia and reperfusion injury . Tin-protoporphyrin . Intercellular adhesion molecule-1 Despite the success of liver transplantation, ischemia and reperfusion (I/R) injury remains a serious problem that affects the outcome in the treatment of patients following hepatectomy and liver transplantation. Although there has been significant effort to identify the mechanisms of reperfusion injury following extended hepatic ischemia, there is no clinically proven means except for the avoidance of warm ischemia and the reduction of cold preservation time. Donor pre-conditioning by ischemic or pharmacological maneuvers has been recently shown to attenuate post-ischemic reperfusion injury in cardiac, renal, and hepatic animal models [15,17,30, 341. The underlying mechanisms may involve the generation of vaso-active molecules such as nitric oxide and adenosine or the expression of stressresponse genes including superoxide dismutase and heat shock proteins (HSPs) [20, 23, 26, 381.

The NRF2 stimulating agent, tin protoporphyrin, activates protective cytokine pathways in healthy human subjects and in patients with chronic kidney disease

“…Despite overwhelming evidence that HO-1 can exert cytoprotective effects, there is a seemingly contradictory literature indicating that within 18-24 hr of SnPP administration, adaptive tissue responses arise which usher in profound tissue protection against superimposed injuries (e.g., ref. Atef, El-Fayoumi, Abdel-Mottaleb, & Mahmoud, 2017;Cukiernik, Mukherjee, Downey, & Chakabarti, 2003;Johnson, Delrow, & Zager, 2017;Johnson & Zager, 2018;Juncos et al, 2006;Kaizu et al, 2003;Panizzon, Dwyer, Nishimura, & Wallis, 1996;Sutherland et al, 2011;Uchida et al, 2003;Zager, 2015;Zager, Johnson, & Frostad, 2016). For example, our laboratory has reported that within 18 hr of SnPP injection, mice develop marked protection against diverse forms of ischemic and toxin-induced AKI (Johnson et al, 2017;Johnson & Zager, 2018;Zager, 2015;Zager et al, 2016).…”