Liver immunolocalization and plasma levels of MMP-9 in non-alcoholic steatohepatitis (NASH) and hepatitis C infection
Introduction
Among the non-alcoholic fatty liver diseases (NAFLD), non-alcoholic steatohepatitis (NASH) represents a severe progressive form of disease. It is recognized as one of the most common causes of chronic liver disease and its prevalence is on the increase worldwide. Although the pathogenesis of NASH is multifactorial, many issues remain unresolved (Shifflet and Wu, 2009). Histologically, the liver of NASH patients is mainly characterized by micro- and macrovesicular steatosis, hepatocyte degeneration and inflammation with leukocyte infiltration. Moreover, it is known that NASH is associated with the activation of liver fibrogenesis (Gramlich et al., 2004; Preiss and Sattar, 2008). Chronic viral infections, such as hepatitis B and C, represent another common cause of persistent liver disease leading to inflammation and fibrosis (Friedman, 2003; Neuman et al., 2008).
Such viral and non-viral diseases are characterized by hepatic remodelling due to an increased synthesis and decreased collagen degradation (Boker et al., 2000). Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been shown to be involved in this remodelling process (Birkedal-Hansen, 1995; Olaso and Friedman, 1998; Clark et al., 2008). MMPs are generally expressed at low levels in normal tissues, but under certain physiological and pathological conditions, they are upregulated (Ries and Petrides, 1995). MMP-9 (gelatinase B; 92-kDa type IV collagenase) is able to degrade gelatins, type III, IV and V collagen and to cleave other matrix and non-matrix molecules with the subsequent release of bioactive molecules (Bergers et al., 2000; Van den Steen et al., 2002; Björklund and Koivunen, 2005).
It is well established that variations of expression of MMPs are correlated to the fibrotic stage of liver diseases. Thus, it is important to understand the mechanisms involved in the participation of MMPs in the course of diseases that induce fibrogenesis. Because of the high risk of progression to cirrhosis and hepatocellular carcinoma by NASH disease (McCullough, 2006), these efforts could eventually lead to development of better diagnoses and new therapeutic strategies.
In this paper we analyzed MMP-9 plasma levels and localization in liver affected with non-alcoholic steatohepatitis, as well as livers with chronic hepatitis C. Both diseases are characterized by progressive development of liver fibrosis, but differences in MMP-9 expression and localization patterns are thought to be related to different physiopathological mechanisms underlying the two diseases.
Section snippets
Patient selection
The present study included 35 patients (19 women and 16 men) with chronic liver disease. Patients, with age range of 21–73 years had not received therapy. 17 patients with NASH were included after liver biopsy and ultrasonography. 18 patients with chronic viral hepatitis C, positive for HCV-RNA in serum and confirmed with biopsy, were included. Patient alcohol consumption had been <20 g/day for the last 5 years. HCV genotype for all patients was 1b. As a representative fibrosis scheme, an
Plasma level determination of MMP-9
Circulating concentrations of MMP-9 in healthy controls, patients with NASH, and patients with HCV are summarized in Figure 1. The mean value of MMP-9 in healthy controls was 39.7 ng/ml (SD: ±4.6). NASH patients showed a higher MMP-9 mean value in comparison to healthy controls: 69.0 ng/ml (SD: ±14.5). Also HCV-infected patients showed an increased mean value of MMP-9 in comparison to healthy controls, reaching a value of 61.7 ng/ml (SD: ±11.0). MMP-9 plasma levels in NASH patients were higher in
Discussion
There are few studies on the expression of MMP-9 in diseases that induce fibrosis in the liver, such as non-alcoholic steatohepatitis and chronic hepatitis C (Kuo et al., 2000; Lichtinghagen et al., 2003; Ljumovic et al., 2004; Núñez et al., 2004). Moreover, MMP-9 immunolocalization studies in chronic liver diseases seem to be lacking. Therefore, we investigated the plasma levels and immunolocalization of MMP-9 in liver biopsies of patients affected with non-alcoholic steatohepatitis and
Acknowledgements
This study was supported by Fondo d’Ateneo per la Ricerca dell’Università di Catania and by funds from Dottorato di Ricerca in Nuovi Sistemi di Valutazione e Studio delle Complicanze Emodinamiche e metaboliche delle Epatopatie Croniche, Università di Catania.
References (42)
- et al.
A critical role for matrix metalloproteinases in liver regeneration
J Surg Res
(2008) Proteolytic remodeling of extracellular matrix
Curr Opin Cell Biol
(1995)- et al.
Gelatinase-mediated migration and invasion of cancer cells
Biochim Biophys Acta
(2005) - et al.
Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions
Am J Gastroenterol
(1999) - et al.
The regulation of matrix metalloproteinases and their inhibitors
Int J Biochem Cell Biol
(2008) - et al.
Pathologic features associated with fibrosis in nonalcoholic fatty liver disease
Hum Pathol
(2004) - et al.
Histological grading and staging of chronic hepatitis
J Hepatol
(1995) - et al.
Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E
Hepatology
(2003) - et al.
Significant differences in serum activities of matrix metalloproteinase-2 and -9 between HCV- and HBV-infected patients and carriers
Clin Chim Acta
(2000) - et al.
Differential expression of matrix metalloproteinases in viral and non-viral chronic liver diseases
Clin Chim Acta
(2004)
Molecular regulation of hepatic fibrogenesis
J Hepatol
Pathogenesis of liver fibrosis: the role of oxidative stress
Mol Aspects Med
Non-alcoholic Steatohepatitis: an overview
J Formos Med Assoc
Expression of immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human normal livers and primary liver tumors
Hepatology
Expression of matrix metalloprotease-2, -7 and -9 on human colon, liver and bile duct cell lines by enteric and gastric Helicobacter species
FEMS Immunol Med Microbiol
Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis
Proc Natl Acad Sci USA
Levels of serum hyaluronic acid, TNF-α and IL-8 in patients with nonalcoholic steatohepatitis
Hepatogastroenterology
Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis
Nat Cell Biol
Tissue inhibitors of metalloproteinases in liver and serum/plasma in chronic active hepatitis C and HCV induced cirrhosis
Hepatogastroenterology
The paradox of matrix metalloproteinases in infectious disease
Clin Exp Immunol
Liver fibrosis – from bench to bedside
J Hepatol
Cited by (18)
MMP-9 activity is increased by adiponectin in primary human hepatocytes but even negatively correlates with serum adiponectin in a rodent model of non-alcoholic steatohepatitis
2011, Experimental and Molecular PathologyCitation Excerpt :Strikingly, hepatic MMP-9 activity even negatively correlates with serum adiponectin. In human NASH MMP-9 is mainly localized to neutrophils (D'Amico et al., 2010) suggesting that its upregulation in NASH liver is partly explained by higher hepatic inflammation, and negative association with systemic adiponectin is therefore in accordance with anti-inflammatory effects of adiponectin (Schaffler et al., 2005;Tilg, 2010). In line with this, probiotics significantly inhibit both, the induction of hepatic fibrosis as well as the increased MMP-2 and MMP-9 expression in the MCD model in mice (Velayudham et al., 2009).
Administration of hydro-alcoholic extract of spinach improves oxidative stress and inflammation in high-fat diet-induced NAFLD rats
2021, BMC Complementary Medicine and Therapies