Sphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: role of S1P signalling and autophagy

Abstract

These studies suggest that S1PL is a novel endogenous suppressor of pulmonary fibrosis in human IPF and animal models.

Microbes Are Associated with Host Innate Immune Response in Idiopathic Pulmonary Fibrosis

“…Integrin alpha(v)beta3, commonly expressed in platelets, is involved in Rho GTPases mediated activation of sphingosine-1-phosphate (S1P) endothelial cell chemotaxis (35) and also acts as a receptor for another gene in the set, Von Willebrand Factor. S1P activity has been shown to be involved in the onset of pulmonary fibrosis (36,37). Interestingly, integrin alpha(v)beta6, also linked to pulmonary fibrosis via Rho-mediated signaling (38)(39)(40) is not included in the magenta module.…”

Sphingosine-1-phosphate metabolism: can its enigmatic lyase promote the autophagy of fibrosis?

“…Furthermore, using S1PL +/− mice they demonstrate increased pulmonary S1P levels, reduced markers of autophagy and an enhanced fibrotic response to bleomycin further supporting a role for S1P and autophagy in the development of tissue fibrosis, and the authors suggest that S1PL is, therefore, an endogenous suppressor of pulmonary fibrosis 15. Intriguingly, however, the authors also demonstrate both TGF-β and bleomycin lead to increased expression of S1PL, and furthermore, that levels of S1PL are increased in lung tissue and lung fibroblasts obtained from patients with IPF.…”

“…This would suggest that if S1PL is an endogenous suppressor of pulmonary fibrosis, in many cases the response is either insufficient or futile in patients with IPF. Fundamentally, the authors show that increased levels of S1PL messenger RNA in peripheral blood mononuclear cells were associated with higher diffusing capacity of lungs for carbon monoxide (DLCO) and improved survival in patients with IPF,15 suggesting that augmenting autophagy in pulmonary fibrosis may be an attractive therapeutic response.…”

“…S1PL inhibitors have recently been developed for the treatment of multiple sclerosis16 and understanding their effects in models of fibrosis will be important in light of the study by Huang et al 15. Therefore, investigating molecules that target the downstream effects of the S1P pathway may hold more promise.…”

“…Over and above the primary mechanistic insights into S1PL in the development of IPF, the paper by Huang et al 15 highlights some important issues in our quest to understand, and better treat, IPF. First, the increased expression of S1PL in IPF does not indicate it is involved in the pathogenesis of disease and emphasises the importance of functional experiments to complement observational studies.…”