HMGB1 in ischemic and non-ischemic liver after selective warm ischemia/reperfusion in rat

Abstract

High mobility group box 1 (HMGB1) acts as an early mediator in inflammation and organ injury. Ischemia reperfusion (I/R) injury induces HMGB1 translocation and expression in ischemic areas. However, it is unknown whether selective warm liver I/R injury also induces the expression of HMGB1 in non-ischemic lobes. The present study aimed to test the hypothesis that selective liver I/R injury also causes HMGB1 translocation and up-regulates its expression in non-ischemic liver areas. In the present study, selective I/R injury was induced by clamping the median and left lateral liver lobes for 90 min followed by 0.5, 6 and 24 h reperfusion. We used male inbred Lewis rats; six animals for each point in time and six animals for the normal control group. Selective hepatic I/R injury induced morphological changes not only in ischemic lobes but also in non-ischemic lobes. HMGB1 translocation and expression was increased in a time-dependent manner in the ischemic lobes, and increased in with delayed onset in the non-ischemic lobes. Serum HMGB1 levels were increased after reperfusion. Furthermore, liver I/R injury up-regulated the expression of HMGB1 receptors (Toll-like receptor 4 and receptor for advanced glycation end products and pro-inflammatory cytokines (Tumor necrosis factor-alpha and interleukin-6) in both ischemic lobes, however, the up-regulation of these cytokines was more prominent in the ischemic lobes. In conclusion, selective warm I/R induces a substantial "sympathetic/bystander" effect on the non-ischemic lobes in terms of HMGB1 translocation and local cytokine production.

HMGB1 in health and disease

“…These events are thought to contribute to the local tissue damage and end-organ injury during I/R in various organs. Increasing evidence suggests that HMGB1 is an important mediator of I/R injury in the liver (Kamo et al, 2013; Liu et al, 2011a; Liu et al, 2014b; Tsung et al, 2007a; Tsung et al, 2005; Watanabe et al, 2005; Yang et al, 2013e), heart (Andrassy et al, 2008; Huang et al, 2007; Kaczorowski et al, 2009a; Oozawa et al, 2008; Zhai et al, 2012), kidney (Chen et al, 2011b; Chung et al, 2008; Rabadi et al, 2012; Wu et al, 2007; Wu et al, 2010), spinal cord (Esposito et al, 2009; Gong et al, 2012; Huang et al, 2011c; Wang et al, 2009c; Zhai et al, 2012; Zhou et al, 2013b), brain (Hayakawa et al, 2008a; Huang et al, 2013b; Kim et al, 2008a; Qiu et al, 2008; Schulze et al, 2013; Tang et al, 2013a), and intestine (Hagiwara et al, 2010a; He et al, 2012a; Kojima et al, 2012b; Tetteh, 2013) and triggers a potentially injurious innate immune response (Kaczorowski et al, 2009b). HMGB1 is also a biomarker of injury in human liver and kidney transplantation (Ilmakunnas et al, 2008; Kruger et al, 2009).…”

Rodent models of hepatic ischemia–reperfusion injury: time and percentage-related pathophysiological mechanisms

“…Serum AST levels also rise at 2 h (3910 IU/L) [52], 5 h and 24 h of reperfusion [49]. Histologically, hemorrhage [50], substantial hepatocellular necrosis [52,53], swelling of hepatocytes [53], slight sinusoidal dilation [53,54] sinusoidal congestion in the centrilobular regions [50], severe cytoplasmic vacuolization [53,54], neutrophilic infiltrates [52] and polymorphonuclear leukocyte infiltration throughout the necrotic areas and sinusoidal spaces [50] are observed. In addition, mean arterial pressure rises and remains high [51].…”

“…Also, TNF-a mRNA expression increases at 30 min, maximizes at 6 h and decreases at 24 h after reperfusion. Finally, IL-6 mRNA levels increase significantly at 30 min and 6 h of reperfusion [53]. Recent data suggest that 70% hepatic ischemia for 90 min followed by reperfusion does not induce 50% mortality [55].…”

Recent progress in histochemistry and cell biology

“…HMGB1 can be passively released by damaged cells or actively secreted by immune cells (including activated Kupffer cells and sinusoidal endothelium cells) and acts as a mediator of inflammation [e.g., involving receptors such as RAGE (Hori et al 1995)] and the family of Toll-like receptors (e.g., Park et al 2006Park et al , 2010. In the context of liver I/R injury and associated increase of HMGB1 expression within ischemic areas and the observation that liver injury can be reduced through the use of a HMGB1 neutralizing antibody (Tsung et al 2005), Liu et al (2011) wanted to investigate HMGB1 expression in non-ischemic liver areas, applying selective warm I/R injury in the rat liver. The authors found that warm I/R injury caused also at non-ischemic sites time-dependent changes with respect to the nuclear-to-cytoplasm translocation of HMGB1 in hepatocytes and increased serum levels.…”