Expression of matrix metalloproteinases and their inhibitors during hepatic tissue repair in the rat

Abstract

Matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs) are thought to play an essential role in liver injury associated with tissue remodeling. However, their distinct expression profile in different liver repair models still remains to be established. Hepatic expression of collagenase (MMP-13), gelatinases A and B (MMP-2, -9), stromelysin-1 and -2 (MMP-3, -10), membrane-type MMP-1 (MMP-14), and TIMP-1 and -2 was studied following single and repeated CCl 4 -mediated injury and after partial hepatectomy. Expression was analyzed by reverse transcription-PCR (RT-PCR), northern blot analysis, zymography, and immunohistochemistry. Following a single toxic liver injury, MMPs and TIMPs were induced in a distinct time frame in that expression of most MMPs was induced during the early phase of liver injury, was maximal during the inflammatory reaction, and was diminished in the recovery phase. In contrast, TIMP and MMP-2 steady state mRNA levels remained constant in the early phase, were strongly induced during tissue inflammation, and remained increased until the recovery phase. Interestingly, hepatic TNF-α expression paralleled the MMP induction profile, while the increase of TGF-β1 expression mapped to the increase of TIMPs. Chronic liver injury was accompanied by an increase in the steady state mRNA levels of MMP-2 and TIMPs, while other MMPs remained more or less unchanged or were diminished. Partial hepatectomy was followed by a dramatic increase of MMP-14 and to a lesser extent also of TIMP-1 expression; other MMPs and TIMPs were not significantly induced. Liver injury is accompanied by profound changes in hepatic MMP/TIMP expression, the latter being critically dependent on the type of injury. Single toxic injury resulting in complete restoration was characterized by a sequential induction of MMPs and TIMPs suggesting initial matrix breakdown and matrix restoration thereafter. Chronic liver injury leading to fibrosis displays overall diminished matrix degradation mainly through TIMP induction, while liver regeneration induced by partial hepatectomy caused an induction of MMP-14 and TIMP-1 only, which might be unrelated to matrix turnover but connected to pericellular fibrinolysis or fibrolysis required for hepatocellular replication.

Rat liver injury following normothermic ischemia is prevented by a phosphinic matrix metalloproteinase inhibitor

“…Two other MMP genes, stromelysin-1 and collagenase-3, were also rapidly induced, with significant levels of RNA detected after 3 h of reperfusion and a peak of expression at 6-24 h followed by a rapid decline. Similar data were obtained in the CCl 4 -mediated liver injury model, and in situ hybridization has shown expression of stromelysin-1 in both hepatocytes and nonparenchymal cells (6,15). Altogether, these results suggest that stromelysin-1, collagenase-3, and gelatinase B are likely to participate in the degradation of liver ECM after I/R and could play an important role during the inflammatory phase ( Fig.…”

“…Important to note is that a similar regulation was also observed for TIMP-2, the third component of the trimeric complex involved in gelatinase A activation. TIMP-1 was induced following liver I/R with an earlier induction after 6 h and a peak of expression at 48 h. These particular patterns of expression (elevation of gelatinase A, MT1-MMP, and TIMP-1 and -2) resembled those previously described during the recovery phase following a single liver injury (15) and in fibrotic livers (5). Liver fibrosis has been extensively studied at the level of matrix degradation or deposition, indicating that in fibrotic liver, collagenolytic activity was decreased and TIMP-1 and -2 as well as gelatinase A expression was elevated (6-8, 10, 11).…”

“…It is interesting that similar MMP expression patterns were observed in different models of injury, including brain, nerves, rat skin wound healing, or toxic injury of the liver (15,29,34,35). The parrallel with the model of single CCl 4 -mediated toxic injury of the liver (15) is particularly interesting because both models are characterized by necrosis and inflammation followed by complete organ restitution.…”

“…It has been shown that stromelysin-1 and TIMP-1 were induced in a distinct time frame during liver regeneration in rats treated with carbon tetrachloride (6,7,13). Regeneration after partial hepactectomy is also followed by a dramatic increase in gelatinase A and B and by an increase in MT1-MMP and TIMP-1 (14,15). Moreover, it has been shown that a single liver injury induced by carbon tetrachloride, which is characterized by hepatocellular necrosis and inflammation before liver regeneration, results in profound changes in MMP and TIMP levels during the acute phase of injury (15).…”

Conditional Tetracycline–Regulated Expression of Tgf–β1 in Liver of Transgenic Mice Leads to Reversible Intermediary Fibrosis

“…In contrast to other models, 45,46 no up-regulation of MMP-9 mRNA was found in induced TA LAP -1/P tet -TGF-␤1 (on)-mice. Because of the shared substrate specificity of MMP-2 and MMP-9, 41 and the remarkably high MMP-2 mRNA induction of up to 21-fold, this difference apparently remains without consequences for the fibrotic process.…”