Hepatocyte NF-κB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia

Abstract

The present study examined the role of hepatocyte NF-kappaB activation during ischemia-reperfusion injury. Second, we evaluated the effects of ischemic hypothermia on NF-kappaB activation and liver injury. C57BL/6 mice underwent 90 min of partial hepatic ischemia and up to 8 h of reperfusion. Body temperature was regulated during the ischemic period between 35 and 37 degrees C, 33 and 35 degrees C, 29 and 33 degrees C or unregulated, where temperature fell to <29 degrees C. Liver injury, as measured by serum alanine aminotransferase as well as liver histopathology, was inversely proportional to regulated body temperature, with the unregulated group (<29 degrees C) being highly protected and the normothermic group (35-37 degrees C) displaying the greatest injury. Inflammation, as measured by production of TNF-alpha and liver recruitment of neutrophils, was greatest in the normothermic groups and lowest in the ischemic hypothermia groups. Interestingly, hepatocyte NF-kappaB activation was highest in the hypothermic group and least in the normothermic group. Paradoxically, degradation of IkappaB proteins, IkappaB-alpha and IkappaB-beta, was greatest in the normothermic group, suggesting an alternate NF-kappaB regulatory mechanism during ischemia-reperfusion injury. Subsequently, we found that NF-kappaB p65 protein was increasingly degraded in normothermic versus hypothermic groups, and this degradation was specific for hepatocytes and was associated with decreased expression of the peptidyl-prolyl isomerase Pin1. The data suggest that NF-kappaB activation in hepatocytes is a protective response during ischemia-reperfusion and can be augmented by ischemic hypothermia. Furthermore, it appears that Pin1 promotes NF-kappaB p65 protein stability such that decreased expression of Pin1 during ischemia-reperfusion results in p65 degradation, reduced nuclear translocation of NF-kappaB, and enhanced hepatocellular injury.

Antioxidant Effects of Xanthohumol and Functional Impact on Hepatic Ischemia−Reperfusion Injury

“…15,20 Therefore, a selective inhibition of NF-κB in the Kupffer cells may be a more promising approach. 41,42 Since it is unlikely that 1 inhibits NF-κB selectively in Kupffer cells, a cell-type-independent and predominant NF-κB inhibition in hepatocytes by xanthohumol might not result in hepatic tissue protection, despite its antioxidant properties.…”

A hősokkfehérjék hatása a máj ischaemiás-reperfúziós károsodására

“…Az NF-κB aktiválódása a teljes májban ischaemia-reperfúzió során a kiterjedt májkáro-sodás jele. Az NF-κB aktivációjának pontos szerepe a májsejtekben I/R során vitatott és mind a védő, mind pedig a káros hatásra vannak bizonyítékok [40]. Az arzenitkezelést követő fokozott HSF1-aktiváció várhatóan csökkenti mind az NF-κB-aktivációt, mind a proinflammátoros citokin felszabadulását, ahogy azt Kuboki és mtsai megfigyelték [14].…”

Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation

“…After 90 min of hypothermic (<29°C) ischemia in mice, NF-κB was increased in hepatocytes, but decreased in Kupffer cells (KCs) (45). The decrease in KC NF-κB activation during hypothermia attenuated TNF-α production compared to the normothermic group, thereby reducing liver injury by avoiding post-ischemic neutrophil accumulation (45).…”

“…After 90 min of hypothermic (<29°C) ischemia in mice, NF-κB was increased in hepatocytes, but decreased in Kupffer cells (KCs) (45). The decrease in KC NF-κB activation during hypothermia attenuated TNF-α production compared to the normothermic group, thereby reducing liver injury by avoiding post-ischemic neutrophil accumulation (45). The increase in hepatocellular NF-κB during ischemia is also advantageous, since it inhibits hepatocyte apoptosis and facilitates liver regeneration by suppressing JNK activity and by driving production of the mitogenic cytokines TNF-α and IL-6, respectively (46).…”