SPHINGOSINE-1-PHOSPHATE AS A KEY INDUCER OF EPITHELIAL MESENCHYMAL TRANSITION IN ASTHMATIC AIRWAYS

The airway epithelium plays a key role in the protection of the internal milieu of the lung1. In this framework, the epithelial-mesenchymal trophic unit (EMTU) controls the local microenvironment ensuring lung tissue homeostasis¹. In asthma alterations of this homeostatic mechanism leads to changes in lung function. In the last years it has become evident a key role for sphingosine-1-phosphate (S1P) in asthma pathogenesis². Alterations in de novo sphingolipid metabolism lead to airway hyperreactivity (AHR), the cardinal feature of asthma, without allergic sensitization or inflammation. Here, we demonstrate that S1P administration to mice affects lung function through activation of EMTU. Bronchi, harvested from S1P-treated mice, present an increased expression of the mesenchymal and fibrosis markers coupled to a reduction of the epithelial ones. EMT well correlates to AHR, pulmonary metaplasia and increased detection of TGF-β/IL33/FGF-2levels in the lung. EMT is reproduced in vitro by incubating airway epithelial cells with either TGF-β or S1P, and it is reversed by pretreatment with LY2109761, a TGF-β antagonist. Accordingly, treatment of mice with LY2109761 abrogates S1P-induced AHR and reverses EMT. Moreover, a sphingosine kinases inhibitor prevents allergen-induced AHR and EMT as well. In conclusion, our data demonstrate that there is a direct correlation between S1P effect on airways and lung dysfunction with an obligatory role of TGF-β. ^1.Lambrecht BN, Hammad H: The airway epithelium in asthma. Nat Med 2012, 18(5):684-92 1 ^2.Ono JG, Worgall TS, Worgall S. Airway reactivity and sphingolipids-implications for childhood asthma. Mol Cell Pediatr. 2015 Dec;2(1):13.