Effect of heat shock preconditioning on NF-κB/I-κB pathway during I/R injury of the rat liver

Abstract

. Effect of heat shock preconditioning on NF-B/I-B pathway during I/R injury of the rat liver. Am J Physiol Gastrointest Liver Physiol 282: G962-G971, 2002. First published January 30, 2002 10.1152/ajpgi.00466.2001.-Hepatic ischemia-reperfusion (I/R) injury continues to be a fatal complication after liver surgery. Heat shock (HS) preconditioning is an effective strategy for protecting the liver from I/R injury, but its exact mechanism is still unclear. Because the activation of nuclear factor-B (NF-B) is an important event in the hepatic I/Rinduced inflammatory response, the effect of HS preconditioning on the pathway for NF-B activation was investigated. In the control group, NF-B was activated 60 min after reperfusion, but this activation was suppressed in the HS group. Messenger RNA expressions of proinflammatory mediators during reperfusion were also reduced with HS preconditioning. Concomitant with NF-B activation, NF-B inhibitor I-B proteins were degraded in the control group, but this degradation was suppressed in the HS group. This study shows that HS preconditioning protected the liver from I/R injury by suppressing the activation of NF-B and the subsequent expression of proinflammatory mediators through the stabilization of I-B proteins.hepatic ischemia-reperfusion; nuclear factor-B proinflammatory mediators AN ORGANISM HAS ENDOGENOUS ability to respond to environmental stresses for survival (37,39). This highly conserved response is called the "stress response" and is associated with the expression of a wide spectrum of proteins related to organic defense mechanisms. For example, the induction of oxygen-free radical scavenging enzymes (12, 26) and several members of the heat shock protein (HSP) family (5, 35, 52), particularly HSP-72, have been noted. HSP-72 functions as a molecular chaperone (23, 25) and contributes to the folding, assembling, and stabilization of intracellular proteins. It is believed that HSP-72 enables an organism to survive noxious stresses (10, 38). We have previously reported that heat shock (HS) preconditioning reduces liver damage caused by ischemia-reperfusion (I/R) injury resulting in a remarkable increase in survival rate (31,44,59,60). We have also demonstrated a correlation between HS preconditioning-induced expression levels of HSP-72 in the liver and resulting tolerance against hepatic I/R injury. I/R injury facilitates the depletion of ATP, the deterioration of intracellular Ca 2ϩ homeostasis (4, 21), the activation of cytotoxic enzymes (proteases, phospholipases, arachidonic acid, etc.) (20), and the generation of reactive oxygen species (ROS) (17). However, little is known about the mechanism with which HS preconditioning or HSP-72 provides protection against hepatic I/R injury.It has recently been shown that several signaling pathways are activated in response to hepatic I/R, and the activated transcription factors induce a variety of cellular gene expressions. For example, nuclear factor-B (NF-B) is a ubiquitous, inducible transcription factor that regulates the ...

Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis

“…Equal loading of protein was determined by Ponceau S staining (Sigma) and by Western blot using a mouse anti-␤-actin antibody (1:5,000 dilution, Sigma). Blotting was performed as described, 22 using rabbit antiheme oxygenase antibody (1:2,000 dilution, Stressgen, Victoria, Canada), rabbit anti-phospho-JNK (c-Jun Nterminal kinase) antibody (1:1,000 dilution, Cell Signaling, Beverly, MA) and an appropriate secondary antibody (1:2,000 dilution, Santa Cruz Biotechnology, Santa Cruz, CA). Protein expression was detected by enhanced chemiluminescence system (Amersham Pharmacia Biotechnology) and visualized using image station 2000R (Kodak, New Haven, CT).…”

NF-κB signaling, liver disease and hepatoprotective agents

“…Moreover, pharmacological inhibitors of IKKb were found effective in preventing hepatic I/R injury (Luedde et al, 2005). Unlike the situation in intestinal I/R, where deletion of IKKb in epithelial cells increased the injury (Chen et al, 2003), strong IKK activation is not seen after hepatic I/R (Uchinami et al, 2002). Curiously, NF-kB activation in response to liver I/R is not mediated by the classical IKKb-dependent pathway, and instead depends on tyrosine phosphorylation of IkBa by Src family members (Fan et al, 2004).…”

Heat Preconditioning Attenuates Renal Injury in Ischemic ARF in Rats

“…Several reports have indicated that the protective effect of HSP-70 is partially mediated through inhibition of NF-B pathway-related inflammation, as well as modulation of cell necrosis or apoptosis (12)(13)(14). Heat preconditioning stabilized IB proteins and subsequently suppressed their activation in liver I/R or myocardial inflammation (15,16). In addition, HSP-70 has been demonstrated to be protective in renal tubular cell apoptosis that is induced by inflammatory cytokine or ATP depletion.…”