Abstract
Bioactive sphingolipids, such as sphingosine 1-phosphate (S1P), dihydrosphingosine 1-phosphate (dhS1P) and ceramide, regulate a diverse array of cellular processes. Many of these processes are important components of wound-healing responses to tissue injury, including cellular apoptosis, vascular leak, fibroblast migration, and TGF-β signaling. Since over-exuberant or aberrant wound-healing responses to repetitive injury have been implicated in the pathogenesis of tissue fibrosis, these signaling sphingolipids have the potential to influence the development and progression of fibrotic diseases. Here we review accumulating in vitro and in vivo data indicating that these lipid mediators can in fact influence fibrogenesis in numerous organ systems, including the lungs, skin, liver, heart, and eye. Targeting these lipids, their receptors, or the enzymes involved in their metabolism consequently now appears to hold great promise for the development of novel therapies for fibrotic diseases.
Highlights
The response to tissue injury involves a complex series of biological responses which, if appropriate in timing, magnitude and balance, restore normal tissue structure and function
We demonstrated that inhibition of sphingosine 1-phosphate (S1P)-S1P1 signaling resulted in increased pulmonary fibrosis in the bleomycin mouse model of this disease, indicating that this pathway functions in the lung as an endogenous inhibitor of fibrogenesis [13]
Numerous studies have shown that sphingolipids, most notably S1P and dihydrosphingosine 1-phosphate (dhS1P), can regulate TGF- signaling pathways in skin cells in vitro, and there are recent data implicating altered sphingolipid signaling in the pathogenesis of human systemic sclerosis (SSc)
Summary
The response to tissue injury involves a complex series of biological responses which, if appropriate in timing, magnitude and balance, restore normal tissue structure and function. Relevant to wound healing and fibrotic responses to tissue injury, S1P signaling through its receptors has been shown to regulate epithelial cell apoptosis, fibroblast migration and myofibroblast differentiation, vascular permeability, and TGF- signaling in vitro [7,8,9,10,11,12].
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