Matrix Metalloproteinases: Regulators of the Tumor Microenvironment

https://www.gastrojournal.org/article/S0016-5085(08)00429-0/pdf

Mechanisms of Hepatic Fibrogenesis

Fibrosis is a highly conserved and co-ordinated protective response to tissue injury. The interaction of multiple pathways, molecules and systems determines whether fibrosis is self-limiting and homeostatic, or whether it is uncontrolled and excessive. Immune cells have been identified as key players in this fibrotic cascade, with the capacity to exert either injury-inducing or repair-promoting effects. A multi-organ approach was recently suggested to identify the core and regulatory pathways in fibrosis, with the aim of integrating the wealth of information emerging from basic fibrosis research. In this Review, we focus on recent advances in liver fibrosis research as a paradigm for wound healing in solid organs and the role of the immune system in regulating and balancing this response.

Liver fibrosis and repair: immune regulation of wound healing in a solid organ

There are two kinds of tutorial articles: those that provide a primer on an established topic and those that let us in on the ground floor of something of emerging importance. The first type of tutorial can have a noted expert who has been gracious (and brave) enough to write a field guide about a particular topic. The other sort of tutorial typically involves researchers who have each been laboring on a topic for some years. Both sorts of tutorial articles are very much desired. But we, as an editorial board for both Systems and Transactions, know that there has been no logical place for them in the AESS until this series was started several years ago. With these tutorials, we hope to continue to give them a home, a welcome, and provide a service to our membership. We do not intend to publish tutorials on a regular basis, but we hope to deliver them once or twice per year. We need and welcome good, useful tutorial articles (both kinds) in relevant AESS areas. If you, the reader, can offer a topic of interest and an author to write about it, please contact us. Self-nominations are welcome, and even more ideal is a suggestion of an article that the editor(s) can solicit. All articles will be reviewed in detail. Criteria on which they will be judged include their clarity of presentation, relevance, and likely audience, and, of course, their correctness and scientific merit. As to the mathematical level, the articles in this issue are a good guide: in each case the author has striven to explain complicated topics in simple-well, tutorial-terms. There should be no (or very little) novel material: the home for archival science is the Transactions Magazine, and submissions that need to be properly peer reviewed would be rerouted there. Likewise, articles that are interesting and descriptive, but lack significant tutorial content, ought more properly be submitted to the Systems Magazine.

What is a tutorial

Models of liver fibrosis, which include cell culture models, explanted and biopsied human material, and experimental animal models, have demonstrated that liver fibrosis is a highly dynamic example of solid organ wound healing. Recent work in human and animal models has shown that liver fibrosis is potentially reversible and, in specific circumstances, demonstrates resolution with a restoration of near normal architecture. This Review highlights the manner in which studies of models of liver fibrosis have contributed to the paradigm of dynamic wound healing in this solid organ.

/pdf/models-of-liver-fibrosis-exploring-the-dynamic-nature-of-17asfalm68.pdf

Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ

https://www.journal-of-hepatology.eu/article/S0168-8278(07)00112-2/pdf

Expression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies

Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain.

Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a crucial role in the pathogenesis of hepatic fibrosis and thus may represent an important therapeutic target in the design of anti-fibrotic strategies for chronic liver disease. We present an innovative therapy based on the assignment of inactivated enzymes acting as scavengers for TIMP-1. Hepatic fibrosis was induced in BALB/c mice by repetitive intraperitoneal CCl4 injection. The animals were treated with proteolytic inactive matrix metalloproteinase-9 mutants (E402Q, H401A, E402H/H411E) using adenovirus-mediated gene transfer. Application of these MMP-9 mutants inhibited fibrogenesis, which was indicated by decreasing portal and periportal accumulation of collagen. Total hydroxyproline of liver tissue, the morphometric stage of fibrosis as well as mRNA expression of marker proteins for hepatic fibrosis in livers of E402Q- and H401A-treated mice were significantly reduced. MMP-9 mutants suppressed transdifferentiation of hepatic stellate cells to the myofibroblast like phenotype in vitro and in vivo. Moreover, adenoviral application of the mutants MMP-9-H401A and -E402Q led to increased apoptosis of activated hepatic stellate cells, thought to be the main promoters of hepatic fibrosis. Application of MMP-9 mutants as TIMP-1 scavengers may provide a new therapeutic strategy for hepatic fibrosis.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.05-4828com

Martin Roderfeld

Papers

Expression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies

Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain.

Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice.

Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice

Matrix metalloproteinase functions in hepatic injury and fibrosis.