Increase of Glycosaminoglycans and Metalloproteinases 2 and 9 in Liver Extracellular Matrix on Early Stages of Extrahepatic Cholestasis

Abstract

-Context -Cholestasis produces hepatocellular injury, leukocyte infiltration, ductular cells proliferation and fibrosis of liver parenchyma by extracellular matrix replacement. Objective -Analyze bile duct ligation effect upon glycosaminoglycans content and matrix metalloproteinase (MMPs) activities. Methods -Animals (6-8 weeks; n = 40) were euthanized 2, 7 or 14 days after bile duct ligation or Sham-surgery. Disease evolution was analyzed by body and liver weight, seric direct bilirubin, globulins, gamma glutamyl transpeptidase (GGT), alkaline phosphatase (Alk-P), alanine and aspartate aminotransferases (ALT and AST), tissue myeloperoxidase and MMP-9, pro MMP-2 and MMP-2 activities, histopathology and glycosaminoglycans content. Results -Cholestasis caused cellular damage with elevation of globulins, GGT, Alk-P, ALT, AST. There was neutrophil infiltration observed by the increasing of myeloperoxidase activity on 7(P = 0.0064) and 14 (P = 0.0002) groups which leads to the magnification of tissue injuries. Bile duct ligation increased pro-MMP-2 (P = 0.0667), MMP-2 (P = 0.0003) and MMP-9 (P<0.0001) activities on 14 days indicating matrix remodeling and establishment of inflammatory process. Bile duct ligation animals showed an increasing on dermatan sulfate and/or heparan sulfate content reflecting extracellular matrix production and growing mitosis due to parenchyma depletion. ConclusionCholestasis led to many changes on rats' liver parenchyma, as so as on its extracellular matrix, with major alterations on MMPs activities and glycosaminoglycans content. HEADINGS -Extrahepatic cholestasis. Glycosaminoglycans. Matrix metalloproteinases.

Chondroitin Sulfate Protects the Liver in an Experimental Model of Extra-Hepatic Cholestasis Induced by Common Bile Duct Ligation

“…Proteoglycans are one of the most important components of liver ECM, mainly constituting glycosaminoglycans (GAGs), dermatan sulfate (DS), heparan sulfate (HS), and minor amounts of CS [ 18 ]. In our previous study, we observed a change in the composition of the ECM in BDL-induced fibrosis, with an increase in DS and HS content after BDL [ 17 ]. Since CS is a molecule naturally present in the body, its supplementation is widely used, especially in the treatment of osteoarthritis due to its anti-inflammatory effect.…”

“…The high density of negative charges due to sulfation and carboxyl groups and many functional domains of CS allow it to interact with several molecules of the ECM [ 16 ]. CS has been reported to play a role in many important biological functions, such as inflammation, cell proliferation, dedifferentiation, migration, tissue morphogenesis, organogenesis, infection, and tissue repair [ 17 , 18 ], and can be considered a compound with a potential protective effect on pathological situations. In the liver, its effect on oxidative stress in an experimental model of CCl 4 -induced hepatotoxicity was demonstrated [ 19 ].…”

SP1 and UTE1 Decoy ODNs inhibit activation and proliferation of hepatic stellate cells by targeting tissue inhibitors of metalloproteinase 1

“…ECM is mainly degraded by MMPs, including MMP2 and MMP9 [ 26 ] and this process can be inhibited by TIMP1 [ 27 ]. TIMP1 transgenic mice hardly engage hepatic fibrosis without any treatment, however, hepatic fibrosis can be induced easily dealing with CCl 4 and an active form of MMP2 level in the liver decreases.…”