The Fibrin-Derived Peptide Bβ15-42 Attenuates Liver Damage in a Rat Model of Liver Ischemia/Reperfusion Injury

Abstract

The inflammatory response after liver ischemia/reperfusion (I/R) contributes to increased risk of liver failure after liver surgery. Strategies aimed to preventing inflammation could be beneficial in reducing liver I/R injury. Recent studies have demonstrated that peptide Bβ15-42 is able to decrease the injury of I/R in heart and kidney by inhibition of leukocyte migration and preserving endothelial barrier function. Prompted by these results, we hypothesized that Bβ15-42 could also possess anti-inflammatory abilities to protect from or reduce hepatic I/R injury. Therefore, in this study, we aimed to evaluate the effects of Bβ15-42 in a model of liver I/R injury in rats. Rats were treated with Bβ15-42 at initiation of reperfusion and 2 h thereafter. Rats were killed at 0.5, 6, 24, and 48 h after reperfusion. Hepatic mRNA levels of fibrinogen-α (Fgα), Fgβ, Fgγ were significantly increased after I/R. Treatment with Fg-derived Bβ15-42 ameliorated liver I/R injury, as indicated by lower serum aminotransferase levels and fewer I/R-associated histopathologic changes. Bβ15-42 treatment decreased leukocyte infiltration and expression of hepatic inflammatory cytokines. Moreover, Bβ15-42 significantly reduced high-mobility group box 1 release and altered mitogen-activated protein kinase activation. In conclusion, Bβ15-42 treatment protected against liver warm I/R injury. The mechanism of protective action of Bβ15-42 seemed to involve its ability to reduce hepatic inflammatory response through preventing high-mobility group box 1 release and altering mitogen-activated protein kinase activation.

HMGB1 in health and disease

“…In addition to liver I/R (Bamboat et al, 2010; Cai et al, 2013; Cardinal et al, 2009; Dhupar et al, 2011; Evankovich et al, 2010; Huang et al, 2013a; Izuishi et al, 2006; Kang et al, 2011a; Li et al, 2013a; Liu et al, 2013b; Nace et al, 2013; Ogiku et al, 2011; Oishi et al, 2012; Tsung et al, 2005; Watanabe et al, 2005; Zeng et al, 2009), transplantation (Ilmakunnas et al, 2008; Kao et al, 2008) and hepatocyte regeneration (Ogiku et al, 2011; Yang et al, 2012g; Zhou et al, 2011b) (discussed above), HMGB1 is implicated in several liver diseases (discussed below) (Chen et al, 2013c). …”

High‐Mobility Group Box‐1 and Liver Disease

“…Additional support for the role of HMGB1 in warm I/R comes from the plethora of compounds targeting HMGB1 signaling that have been found to successfully ameliorate injury . Thus, the role of hepatic HMGB1 in warm I/R is still contradictory.…”

“…(144) Additional support for the role of HMGB1 in warm I/R comes from the plethora of compounds targeting HMGB1 signaling that have been found to successfully ameliorate injury. (32,(145)(146)(147)(148)(149)(150) Thus, the role of hepatic HMGB1 in warm I/R is still contradictory. To clarify whether it amplifies or ameliorates injury or has no involvement whatsoever, as one study claims, (74) more research is essential.…”

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

“…Recent studies show that Bβ15-42 (the fibrin-derived peptide), PNU-282987 (a selective α7 nicotinic acetylcholine receptor agonist), EPC-K1 (the vitamin E derivative), melatonin, cisplatin and glycyrrhizin attenuate warm liver I/R damage partly through inhibition of HMGB1 release (47)(48)(49)(50)(51)(52). Interestingly, pretreatment of mice with HMGB1 protein significantly decreased liver I/R injury through upregulation of IL-1R-associated kinase-M, a negative regulator of TLR4 signaling (53).…”