Published ahead of print on February 22, 2007, doi:10.1165/rcmb.2006-0383OC Am. J. Respir. Cell Mol. Biol., Volume 36, Number 6, June 2007, 757-762 A more recent version of this article appeared on June 1, 2007
Submitted on October 12, 2006 Sphingosine-1-phosphate/Sphingosine Kinase Pathway is Involved in Mouse Airway Hyper-responsivenessFiorentina Roviezzo1,1 Dipartimento di Farmacologia Sperimentale, Universita di Napoli Federico II, Napoli, Italy, 2 Dipartimento di Medicina Sperimentale, Sezione di Farmacologia L. Donatelli, Seconda Universita degli Studi di Napoli, Napoli, Italy, 3 Dipartimento di Internistica Clinica e Sperimentale, Seconda Universita di Napoli, Napoli, Italy * To whom correspondence should be addressed. E-mail: cirino{at}unina.it.
Rationale: Sphingosine-1-phosphate (S1P) has been shown to regulate numerous and diverse cell functions, including smooth muscle contraction. Here we assessed the role of S1P/Sphingosine kinase (SPK) pathway in regulation of bronchial tone. Objectives: to determine using an integrated pharmacological and molecular approach i) the role of S1P as endogenous modulator of the bronchial tone ii) the linkage between S1P pathway and bronchial hyperresponsiveness. Methods: we evaluated S1P effects on isolated bronchi and whole lungs, harvested from Balb/c mice sensitised to ovalbumin versus vehicle treated mice, by measuring bronchial reactivity and lung resistance. Main results: S1P administration on non-sensitized mouse bronchi does not cause any direct effect on bronchial tone, while a significant increase in Ach-induced. contraction occurs following S1P challenge. Conversely, in ova-sensitized mice S1P/SPK pathway triggers airway hyperesponsiveness. Indeed, S1P causes a dose dependent contraction of isolated bronchi. Similarly in the whole lung system S1P increased airway resistance only in ova sensitized mice. The action on bronchi of S1P is coupled to an enhanced expression of SPK1 and SPK2 as well as of S1P2 and S1P3 receptors. In these experiments the key role for S1P/SPK in hyperreactivity has been confirmed by pharmacological modulation of SPKs. Conclusions: S1P/SPK pathway does not seem to play a major role in physiological conditions, while it may become critical in pathological conditions. These results open new windows for therapeutic strategies in diseases like asthma.
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