Mechanical stretch induces matrix metalloproteinase 1 production in human hepatic stellate cells
Introduction
Hepatic stellate cells (HSC), which correspond to pericytes surrounding capillaries, are located within the subendothelial space of Disse, are characterized by long, branching processes and take part in the pathogenesis of liver disease [1], [2]. Hepatic stellate cells store retinyl palmitate, deliver retinol to extrahepatic tissues, regulate sinusoidal microcirculation, synthesize extracellular matrix proteins, and participate in fibrotic scarring in chronic hepatic diseases.
In chronic hepatic diseases, especially liver cirrhosis, portal hypertension is one of the most important complications. The pressure gradient within the portal venous system is a product of vascular resistance (backward flow theory) [3], [4] and portal blood flow (forward flow theory) [5], [6]. Increasing portal blood flow, HSC may be lengthened in response to mechanical stretch stimulation and their function may be changed.
Hepatic fibrosis results from a relative imbalance between synthesis and degradation of matrix proteins. In liver injury, both the amount and relative composition of the hepatic extracellular matrix are altered. Matrix metalloproteinases (MMP) have a function in the turnover of extracellular matrix components such as collagens, proteoglycans, elastin, laminin, fibronectin, and other glycoproteins, while tissue inhibitors of metalloproteinases (TIMP) are low-molecular weight proteins that inhibit MMP in a 1:1 molar ratio [7], [8]. Iredale et al. reported that TIMP1 expression increased relative to MMP1 and TIMP1 expression and preceded procollagen 1 expression in liver after bile duct ligation and carbon tetrachloride administration [9]. Herbst et al. reported that HSC expressed increased encoding of TIMP1 and TIMP2 mRNA in liver fibrosis and in vitro, TGF-β1 enhanced expression of TIMP1 and MMP2 mRNA [10]. HSC, then, produce MMP and TIMP, shifting their balance in many kinds of liver injury.
MMP1, also termed interstitial collagenase, degrades collagens I, II, III, VII, and X as well as gelatins, entactin, aggrecan, and link protein. MMP2, or gelatinase A, degrades gelatins, collagens I, IV, V, VII, X, and XI, fibronectin, laminin, aggrecan, elastin, large tenascin C, and vitronectin. MMP2 also degrades β-amyloid protein precursor, thus showing β-secretase-like activity [8]. Type I and type III collagen accounts for about 85% of all extracellular matrix protein in the liver. Okazaki et al. reported that collagenase activity increased and MMP1 played an important role in experimental hepatic fibrosis [11].
Previous studies have revealed a relationship between mechanical stretch and matrix metalloproteinases and tissue inhibitors of metalloproteinases in many kinds of cultured cells. However, little is known about the influence of mechanical stretch stimulation on production of MMP and TIMP in HSC, which play an important role in hepatic fibrosis. Therefore, we examined production of MMP, TIMP, and extracellular matrix by HSC to investigate the relationship between mechanical stretch and hepatic fibrosis.
Section snippets
Cell culture
We used a cultured human hepatic stellate cell line, LI90 (provided by Dr. Tomokazu Matsuura), in this study. This cell line, established by Murakami et al. from an epithelioid hemangioendothelioma arising in human liver, is well characterized as consisting of HSC-like cells that lack characteristics of endothelial cells or macrophages [12]. LI90 cells had a polygonal shape, had well developed α-smooth muscle actin filaments in their cytoplasm, and produced various connective tissue components,
Morphological change of stretched LI90 cells
In phase-contrast microscopic studies, LI90 cells stretched for 24 h were narrower than unstretched cells and showed a finer network of processes (Fig. 1).
Concentration of MMP1, MMP2, TIMP1, and TIMP2 in culture supernatants of LI90 cells
The concentration of MMP1 in culture supernatants showed an increase in stretched as opposed to unstretched LI90 cells, while in contrast the concentrations of MMP2, TIMP1, and TIMP2 showed a decrease in stretched cells compared to unstretched cells: MMP1 in unstretched cells, 197.8 ± 23.0 ng/ml, and stretched cells, 224.8 ± 13.9 ng/ml (p < 0.05);
Discussion
Portal hypertension, which results from increased intrahepatic resistance to blood flow after liver injury, is a major complication of scarring in the liver. Von Leeuwen et al. reported Disse's space was significantly increased in patients with chronic active hepatitis (CAH), CAH in transition to cirrhosis, and cirrhosis compared with near normal subjects [15]. In the hyperdynamic portal circulation and increase Disse's space, HSC may be exposed to mechanical stress caused by congested blood
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