Antagonization of TIMP–1 Induces Apoptosis in Activated Hepatic Stellate Cells

Aims: The first pathological implication of chronic toxic liver injury including alcoholism is subsequent cell damage or cell death which results in transdifferentiation of HSC into the myofibroblast phenotype. Activated hepatic stellate cells (HSC) accelerate production of ECM, TIMPs, cytokines, and several MMPs promoting hepatic fibrogenesis. TIMP–1 was found to suppress apoptosis in activated HSC1. Our approach was to antagonize TIMP–1 by proteolytically inactive MMP–9 mutants in order to induce HSC apoptosis and thus to reduce hepatic fibrogenesis.