Mechanisms of Fibrolysis in Chronic Liver Injury (with Special Emphasis on MMPs and TIMPs)

Zusammenfassung

Die Regeneration der fibrotischen Leber ist durch vier Mechanismen charakterisiert: 1. Aussetzen des schädigenden Agens, 2. Apoptose aktivierter hepatischer Sternzellen, 3. Umbau der extrazellulären Matrix und 4. Regeneration des Parenchyms und damit: Wiederherstellung normaler Leberfunktionen. Für den Umbau der extrazellulären Matrix ist die zeitlich und räumlich abgestimmte Regulation der proteolytischen Aktivität der Matrix-Metalloproteinasen (MMPs) und die Expression ihrer spezifischen Inhibitoren, der Tissue Inhibitors of Metalloproteinases (TIMPs) essenziell. Aktuelle Erkenntnisse über Mechanismen der hepatischen Fibrolyse mit dem Schwerpunkt „MMPs und TIMPs” werden diskutiert. Die Expressionsmuster von MMPs und TIMPs während der hepatischen Fibrogenese und Fibrolyse, Gen- und Proteinregulation, an der Expression beteiligte Zelltypen und bisher untersuchte Krankheitsbilder und Modelle werden kritisch beleuchtet. Insbesondere Studien, die einen zeitlichen Verlauf der Expression von MMPs und TIMPs während der Fibrogenese beschreiben, wurden analysiert, um Homologien im Expressionsmuster der beteiligten Faktoren herauszustellen.

Abstract

Regeneration from liver fibrosis is characterized by four essential events: 1. eradication of pathological agents, 2. apoptosis of activated hepatic stellate cells, 3. remodeling of extracellular matrix, and 4. regeneration of parenchyma and liver function. The temporal and spatial regulation of matrix metalloproteinase (MMP) activity and expression of their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play a pivotal role in matrix remodeling during hepatic fibrogenesis and recovery. According to current knowledge, the main topics and mechanisms in regeneration from hepatic fibrosis with special emphasis on MMPs and TIMPs are presented. MMP and TIMP expression patterns during hepatic fibrogenesis and fibrolysis, specific characteristics like regulation, expression of cell types, gene expression (RNA/protein), and the underlying disease are summarized. Studies presenting a time course for MMP and TIMP expression during recovery from hepatic fibrosis were taken into consideration to point out a synchronizing behavior in the expression pattern.

Schlüsselwörter

Leber - hepatische Fibrose - Fibrolyse - MMP - TIMP - Matrix-Metalloproteinase - hepatische Stern-Zelle

Key words

liver - hepatic fibrosis - fibrolysis - MMP - TIMP - matrix metalloproteinase - hepatic stellate cell

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