Patients with chronic liver disease frequently progress to fibrosis and finally cirrhosis. Cirrhosis is the most important determinant of liver-related mortality. At present there exists no proven therapy to halt fibrosis progression or to reverse cirrhosis. Activated hepatic stellate cells and myofibroblasts (collectively termed HSC) produce most of the scar tissue in liver fibrosis and thus drive fibrogenesis. During early activation the same cells also express the enzymes that dissolve scar components, such as certain matrix metalloproteinases (MMPs). While fibrogenic activation of HSC is fairly well defined, their potential to dissolve scar tissue, i.e., to induce fibrolysis, is largely unexplored. We have shown that 1) cell membrane derived microparticles (MP) from apoptotic or activated T cells but not from hepatocytes induce the expression of fibrolytic MMPs in HSC;2) these MP fuse with HSC cell membranes;3) fibrolytic gene expression is triggered via activation of Erk1/2, nuclear factor kappa B (NFkB) and p38 kinase l;and 4) MP contain membrane molecules that are likely candidates of HSC fibrolytic activation. The central hypothesis of this proposal is that MP released from T-cells can induce a fibrolytic phenotype in HSC, potentially reversing liver fibrosis and cirrhosis. Our goals are 1) to identify T cell subsets that generate the most effective fibrolytic MP, and 2) to identify the molecules and signal transduction pathways by which MP induce fibrolytic genes.
Aim 1 will study the effect of MP released from activated T-cell subpopulations on the fibrogenic/fibrolytic phenotype of HSC. T cells will be CD4+, CD8+, CD25+, and Th1 or Th2 T- polarized.
Aim 2 will identify the molecules and examine the signal transduction pathways that lead to acquisition of a fibrolytic phenotype by HSC exposed to MP. Our proposed studies will provide information on the contribution of MP to fibrolytic activation of HSC, and their potential role in favorable architectural remodeling of the fibrotic liver. The information gained will also impact on the understanding of fibrolysis in other organ pathologies which have chronic inflammation as a common feature. Our long-term goal is to explore novel MP-based strategies to treat advanced hepatic fibrosis.
