Effects of silymarin and pentoxifylline on matrix metalloproteinase-1 and -2 expression and apoptosis in experimental hepatic fibrosis

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dc.contributor.authorKara E.
dc.contributor.authorCoşkun T.
dc.contributor.authorKaya Y.
dc.contributor.authorYumuş O.
dc.contributor.authorVatansever S.
dc.contributor.authorVar A.
dc.date.accessioned2024-07-22T08:22:02Z
dc.date.available2024-07-22T08:22:02Z
dc.date.issued2008
dc.description.abstractBackground: Many therapeutic strategies have been proposed to treat liver fibrosis, but no drugs have been proved effective. Matrix metalloproteinases (MMPs) have been reported to play a role in some cellular cascades of hepatic inflammation and fibrosis. Objective: The purpose of this study was to investigate whether silymarin and pentoxifylline (PTX) have hepatoprotective and antifibrotic effects in experimental hepatic fibrosis. Methods: Sprague-Dawley rats were divided into 4 groups: silymarin group (silymarin 4 mg/kg · d-1 orally, common bile duct ligation [CBDL]); PTX group (PTX 2 mg/kg · d-1 intraperitoneally, CBDL); sham group (common bile duct [CBD] exploration only); and control group (saline 1 mL/d orally, CBDL). The CBD was explored and dissected sufficiently to allow passage of a 3/0 silk suture via midline laparotomy. On day 10, all animals were euthanized via cervical dislocation. Then, 5-cm3 liver samples from the right lobe were removed for histomorphologic evaluation and 3-mL blood samples were taken via cardiac puncture for biochemical analyses. Apoptosis was determined using the terminal deoxynucleotidyltransferase-biotin nick end-label (TUNEL) staining method. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase; total and indirect bilirubin concentration; hepatic MMP-1 and -2 and tissue inhibitor of MMP (TIMP)-l and -2 activity; and transforming-growth factor (TGF)-β1 concentration were measured. Collagen content was determined by measuring hydroxyproline in liver samples. Malondialdehyde (MDA) was used to estimate lipid peroxidation. Results: Thirty-two adult male Sprague-Dawley rats were divided into 4 groups: silymarin group (n = 7), PTX group (n = 7), sham group (n = 9), and control group (n = 9). Compared with the control group (14.6 [2.44]), mean (SD) hepatocyte apoptosis (as measured by the ratio of TUNEL-positive cells) was significantly suppressed in the silymarin group (1.2 [0.13]; P = 0.001) and the PTX group (3.8 [0.34]; P = 0.001). Mean (SD) MMP-2 activity in the silymarin group (57.35 [9.89] μg/mL; P = 0.04) and the PTX group (46.88 [9.56] μg/mL; P = 0.04) was significantly lower than that observed in the control group (232.32 [79.76] μg/mL). Compared with the control group (1.37 [0.38] μg/mL), TIMP-2 activity was significantly lower in the silymarin group (0.55 [0.13] μg/mL; P = 0.04) and the PTX group (0.42 [0.09] μg/mL; P = 0.01). Compared with the control group (909.17 [117.35] μg/mL), TGF-β1 was significantly lower in the silymarin group (518.24 [30.34] μg/mL; P = 0.01) and the PTX group (519.57 [47.27] μg/mL; P = 0.01). Histomorphologic changes were significantly greater in the sham group than in the silymarin and PTX groups: hemorrhage (2.44 [0.29] vs 1.29 [0.18] and 1.57 [0.20], respectively; both, P = 0.04); sinusoidal dilatation (2.22 [0.22] vs 1.57 [0.20] and 1.71 [0.18]; both, P = 0.04); presinusoidal polymorphonuclear cell infiltration (3-44 [0.24] vs 2.57 [0.20] and 2.14 [0.26]; P = 0.03 and P = 0.008, respectively); and inflammation (3.44 [0.24] vs 2.57 [0.20] and 2.14 [0.26]; P = 0.03 and P = 0.008, respectively). In the control group, all biochemical markers were elevated, supporting the presence of liver injury. Compared with the control group (630.00 [46.80] U/L), plasma AST activity was significantly lower in the silymarin group (443.11 [78.73]; P = 0.04) and the PTX group (349.42 [34.00]; P = 0.03). Compared with the control group (191.12 [32.93] U/L), plasma ALT activity was significantly lower in the silymarin group (86.14 [4.97]; P = 0.04) and the PTX group (84.14 [11.21]; P = 0.04). MDA concentration was significantly lower in the silymarin group compared with the control group (0.08 [0.01] vs 0.22 [0.03] nmol/mL; P = 0.004); MDA was also significantly lower in the silymarin group than in the PTX group (0.11 [0.02]; P = 0.03). Conclusions: Silymarin and PTX were associated with lower histopathologic liver damage, hepatocyte apoptosis, and regulation of extracellular matrix proteins. Lipid peroxidation in hepatocytes was significantly lower in the silymarin group compared with the PTX group. Silymarin and PTX appeared to have hepatoprotective effects in this experimental liver fibrosis model, but further clinical and experimental studies are needed. © 2008 Excerpta Medica Inc. All rights reserved.
dc.identifier.DOI-ID10.1016/j.curtheres.2008.12.003
dc.identifier.issn0011393X
dc.identifier.urihttp://akademikarsiv.cbu.edu.tr:4000/handle/123456789/18880
dc.language.isoEnglish
dc.rightsAll Open Access; Gold Open Access
dc.subjectalanine aminotransferase
dc.subjectaspartate aminotransferase
dc.subjectbilirubin
dc.subjectcollagen
dc.subjectgamma glutamyltransferase
dc.subjectgelatinase A
dc.subjecthydroxyproline
dc.subjectinterstitial collagenase
dc.subjectmalonaldehyde
dc.subjectpentoxifylline
dc.subjectsilymarin
dc.subjectsodium chloride
dc.subjecttissue inhibitor of metalloproteinase 1
dc.subjecttissue inhibitor of metalloproteinase 2
dc.subjecttransforming growth factor beta1
dc.subjectalanine aminotransferase blood level
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectapoptosis
dc.subjectarticle
dc.subjectaspartate aminotransferase blood level
dc.subjectbile duct ligation
dc.subjectbilirubin blood level
dc.subjectcell infiltration
dc.subjectcontrolled study
dc.subjectdrug activity
dc.subjectenzyme activity
dc.subjectgamma glutamyl transferase blood level
dc.subjecthistopathology
dc.subjectlipid peroxidation
dc.subjectliver cell
dc.subjectliver fibrosis
dc.subjectliver hemorrhage
dc.subjectliver protection
dc.subjectliver sinusoid
dc.subjectmale
dc.subjectnonhuman
dc.subjectpolymorphonuclear cell
dc.subjectpriority journal
dc.subjectprotein expression
dc.subjectrat
dc.titleEffects of silymarin and pentoxifylline on matrix metalloproteinase-1 and -2 expression and apoptosis in experimental hepatic fibrosis
dc.typeArticle

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