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Fibrosis Overview

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Fibrosis Overview

Although fibrogenesis is increasingly recognized as a major cause of morbidity and mortality, there are few—if any—treatment strategies that specifically target the mechanisms of fibrosis, despite the fact that nearly 45 percent of all deaths in the developed world are attributable to progressive fibroproliferative disease.”

    Thomas A. Wynn, Ph.D.
    Chief, Immunopathogenesis Section, LPD
    Scientific Director, NIH-Oxford-Cambridge Scholars Ph.D. Program

Fibrosis is the excess production of connective tissue in an organ or tissues.  It is characterized by the production of extracellular matrix (ECM) made up mainly of collagen and fibronectin.  Chronic diseases characterized by fibrosis share a common mechanism.  Repeated injury to an organ or tissue results in the activation and proliferation of fibroblasts and myofibroblasts, which in turn cause the deposit of ECM.  Inflammatory signaling involving transforming growth factor-beta (TGFβ tumor necrosis factor alpha (TNFα) and sphingosine 1 phospate (S1P) are also implicated in the process.

A number of therapeutic approaches have been investigated for the treatment of fibrosis including RhoA kinase (ROCK) inhibition and antibodies to bind to circulating TGFβ, TNFα or S1P. 

The sphingosine 1-phosphate receptor 2 (S1PR2) mitigates many of the effects of these important signaling peptides.  S1PR2 inhibition via RhoA and ROCK inhibits TNFα production.  The S1PR2 inhibition also decreases the TGFβ cell signalling effects on S1P production and ERK1/2 -MAP kinase mediated fibrosis. See chart below:

FibrosisPatheway

Scheme 1: The central role of Sphingosine 1-phosphate receptor 2 in fibrosis

S1PR2 is one of five S1P g-coupled receptors. The S1PR2 signaling pathway is also involved in inhibiting diverse cell migration, and promoting or inhibiting angiogenesis, both in normal or aberrant pathologies. The role of the S1PR2 in inflammation and cancer is an active area of research.
 

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