Osteopontin deficiency aggravates hepatic injury induced by ischemia–reperfusion in mice

Abstract

Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia–reperfusion (I–R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn−/− mice compared with wild-type (Wt) mice after I–R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn−/− mice versus Wt mice after I–R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen–glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn−/− mice versus Wt mice livers after I–R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I–R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.

Osteopontin directly modulates cytokine expression of primary microglia and increases their survival

“…Pharmacological blockade of iNOS attenuates microglia activation and the expression of TNF and IL-1 in the thalamus of OPN-deficient mice (Schroeter, Zickler, 2006). In a macrophage cell line, downregulation of OPN enhances iNOS expression and leads to an upregulation of iNOS, TNF-α and IL-6 in response to lipopolysaccharides (Patouraux et al , 2014). In porcine microglia, OPN inhibits superoxide production induced by stimulation with phorbol-myristate-acetate (Tambuyzer, Casteleyn, 2012).…”

Neutralization of Osteopontin Ameliorates Acute Lung Injury Induced by Intestinal Ischemia-Reperfusion

“…In support of this notion, Zhang et al have revealed that OPN expression was increased in renal tubular epithelial cells after renal I/R in mice, which resulted in exaggerated initial inflammatory responses as mediated by the NK cell activation (31). In contrast to renal ischemia model, recent study has also demonstrated an upregulation of OPN expression in the liver tissues and plasma after hepatic I/R which were shown to play protective functions in hepatic injury and inflammation by its ability to partially prevent death of hepatocytes and to limit the production of toxic inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) by macrophages (32). Thus, the data from the above studies may suggest that OPN might play dual roles depending on ischemia and reperfusion models adopted in various organs.…”

Serum osteopontin is a predictor of prognosis for HBV‑associated acute‑on‑chronic liver failure

“…A number of studies have suggested that OPN may serve as a biomarker of severe fibrosis and portal hypertension during Schistosomiasis mansoni (8) and chronic viral hepatitis (9,10). Nevertheless, in mice models of liver injury induced by diethylnitrosamine or ischemia/reperfusion, OPN exerted a protective effect by ameliorating the production of IL-6 and TNF-α in macrophages and inhibiting inflammation (11,12). Furthermore, OPN may serve a key role in the expansion of hepatic progenitor cells (HPC) and in promoting liver regeneration during liver cancer (13,14) and acute liver failure (15,16).…”