Liver fibrosis secondary to bile duct injury: correlation of Smad7 with TGF-β and extracellular matrix proteins

Abstract

BackgroundLiver fibrosis is the result of continuous liver injury stemming from different etiological factors. Bile duct injury induces an altered expression of TGF-β, which has an important role in liver fibrosis because this cytokine induces the expression of target genes such as collagens, PAI-1, TIMPs, and others that lead to extracellular matrix deposition. Smad7 is the principal inhibitor that regulates the target gene transcription of the TGF-β signaling. The aim of the study was to determine whether Smad7 mRNA expression correlates with the gene expression of TGF-β, Col I, Col III, Col IV, or PAI-1 in liver fibrosis secondary to bile duct injury (BDI).ResultsSerum TGF-β concentration was higher in BDI patients (39 296 pg/ml) than in liver donors (9008 pg/ml). Morphometric analysis of liver sections showed 41.85% of tissue contained fibrotic deposits in BDI patients. mRNA expression of Smad7, Col I, and PAI-1 was also significantly higher (P < 0.05) in patients with BDI than in controls. Smad7 mRNA expression correlated significantly with TGF-β concentration, Col I and Col III expression, and the amount of fibrosis.ConclusionWe found augmented serum concentration of TGF-β and an increase in the percentage of fibrotic tissue in the liver of BDI patients. Contrary to expected results, the 6-fold increase in Smad7 expression did not inhibit the expression of TGF-β, collagens, and PAI-1. We also observed greater expression of Col I and Col III mRNA in BDI patients and significant correlations between their expression and TGF-β concentration and Smad7 mRNA expression.

Alterations in fibrinolytic system proteins PAI-1, MMP-3, MMP-8, TIMP-1 and TIMP-2 in post-cholecystectomy bile duct injury

“…TGF-β is a multifunctional cytokine involved in regulation, differentiation, and proliferation of ECM. TGB-β also has an important role in hepatic fibrogenesis since it activates the over expression of ECM deposits through molecules like PAI-1, TIMPs, collagens, tenascin, fibronectin, and Smad7, as previously reported by our group [25]. In the present study, plasma levels of PAI-1 were higher in BDI compared to healthy controls, which could explain the activation and facilitation of the fibrous tissue deposition in the liver with BDI as well as the very important role PAI-1 has in inhibiting the activation of MMP-3 upon favouring activation of TIMPs [26].…”

TGF-β and TGF-β/Smad Signaling in the Interactions between Echinococcus multilocularis and Its Hosts

“…In physiological situations, its increase decreases the phosphorylation of Smad2/3, and thus decreases TGF- β functions. In chronic hepatic injury, the expression of Smad7 is paradoxically decreased [38]; as a result, TGF- β signal transduction cannot be effectively inhibited, and TGF- β functions are enhanced. An aberrant expression of Smad7 may thus disrupt the balanced activity of TGF- β under pathophysiological conditions.…”

Manual therapy as an effective treatment for fibrosis in a rat model of upper extremity overuse injury

“…The Videocount Area Array option of the software was also utilized (defined as the number of pixels in a field that met a user-defined color threshold of staining). The number of thresholded blue pixels in each field were then counted and analyzed as a percentage of the total number of pixels in that field, using similar methods as previously described for liver fibrosis (del Pilar Alatorre-Carranza, Miranda-Diaz et al 2009). For the glabrous region of dermis of the mid forepaw, 3 to 4 fields were counted per animal (in cross-sectional tissue slices) using a 20X objective, and the % area of blue staining (fibrous collagen) was averaged for each animal, before comparing results across groups.…”