Details

Autor(en) / Beteiligte

• Di Sario, Antonio
• Bendia, Emanuele
• Taffetani, Silvia
• Marzioni, Marco
• Candelaresi, Cinzia
• Pigini, Paola
• Schindler, Ursula
• Kleemann, Heinz-Werner
• Trozzi, Luciano
• Macarri, Giampiero
• Benedetti, Antonio

Titel

Selective Na +/H + exchange inhibition by cariporide reduces liver fibrosis in the rat

Ist Teil von

• Hepatology (Baltimore, Md.), 2003-02, Vol.37 (2), p.256-266

Ort / Verlag

Philadelphia, PA: Elsevier Inc

Erscheinungsjahr

2003

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• The aim of this study was to evaluate the effect of cariporide, a selective Na +/H + exchange inhibitor, on isolated and cultured hepatic stellate cells (HSCs) and in 2 in vivo models of rat liver fibrosis. Platelet-derived growth factor (PDGF)-induced HSC proliferation, evaluated by measuring the percentage of bromodeoxyuridine-positive cells, was significantly inhibited by cariporide, with a maximal effect at 10 μmol/L. Incubation with cariporide did not inhibit PDGF-induced extracellular-regulated kinase 1/2 (ERK1/2), Akt (a downstream component of the phosphatidylinositol [PI]-3 kinase pathway), and protein kinase C (PKC) activation but reduced PDGF-induced activation of the Na +/H + exchanger, with a maximal effect at 10 μmol/L. Rats treated with dimethylnitrosamine (DMN; 10 mg/kg) for 1 and 5 weeks received a diet with or without 6 ppm cariporide. Treatment with cariporide reduced the degree of liver injury, as determined by alanine aminotransferase (ALT) values, also when administered after the induction of hepatic damage. This was associated with reduced HSC activation and proliferation and reduced collagen deposition, as determined by morphometric evaluation of α–smooth muscle actin (SMA)/proliferating cell nuclear antigen–positive cells and percentage of Sirius red–positive parenchyma, respectively. Moreover, cariporide was also able to reduce α(1)I procollagen messenger RNA (mRNA) expression. Similar effects were observed in bile duct–ligated (BDL) rats. In conclusion, selective inhibition of the Na +/H + exchanger by cariporide may represent an effective therapeutic strategy in the treatment of hepatic fibrosis. (H EPATOLOGY 2003;37:256-266.)