title: A Phosphorylatable Sphingosine Analog Induces Airway Smooth Muscle Cytostasis and Reverses Airway Hyperresponsiveness in Experimental Asthma.
abstract: In asthma, excessive bronchial narrowing associated with thickening of the airway smooth muscle (ASM) causes respiratory distress. Numerous pharmacological agents prevent experimental airway hyperresponsiveness (AHR) when delivered prophylactically. However, most fail to resolve this feature after disease is instated. Although sphingosine analogs are primarily perceived as immune modulators with the ability to prevent experimental asthma, they also influence processes associated with tissue atrophy, supporting the hypothesis that they could interfere with mechanisms sustaining pre-established AHR. We thus assessed the ability of a sphingosine analog (AAL-R) to reverse AHR in a chronic model of asthma. We dissected the pharmacological mechanism of this class of agents using the non-phosphorylatable chiral isomer AAL-S and the pre-phosphorylated form of AAL-R (AFD-R)in vivoand in human ASM cells. We found that a therapeutic course of AAL-R reversed experimental AHR in the methacholine challenge test, which was not replicated by dexamethasone or the non-phosphorylatable isomer AAL-S. AAL-R efficiently interfered with ASM cell proliferationin vitro, supporting the concept that immunomodulation is not necessary to interfere with cellular mechanisms sustaining AHR. Moreover, the sphingosine-1-phosphate lyase inhibitor SM4 and the sphingosine-1-phosphate receptor antagonist VPC23019 failed to inhibit proliferation, indicating that intracellular accumulation of sphingosine-1-phosphate or interference with cell surface S1P1/S1P3activation, are not sufficient to induce cytostasis. Potent AAL-R-induced cytostasis specifically related to its ability to induce intracellular AFD-R accumulation. Thus, a sphingosine analog that possesses the ability to be phosphorylatedin situinterferes with cellular mechanisms that beget AHR.
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec QC, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Gendron
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec QC, Canada.
authors.forename: Pascale B
authors.initials: PB
authors.lastname: Lecours
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec QC, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lemay
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec QC, Canada.
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Beaulieu
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec QC, Canada.
authors.forename: Carole-Ann
authors.initials: CA
authors.lastname: Huppé
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec QC, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Lee-Gosselin
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QuébecQC, Canada; Faculty of Medicine, Université Laval, QuébecQC, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Flamand
authors.affiliation: Centenary Institute and NHMRC Clinical Trials Centre, University of Sydney, Camperdown NSW, Australia.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Don
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QuébecQC, Canada; Faculty of Medicine, Université Laval, QuébecQC, Canada.
authors.forename: Élyse
authors.initials: É
authors.lastname: Bissonnette
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QuébecQC, Canada; Faculty of Medicine, Université Laval, QuébecQC, Canada.
authors.forename: Marie-Renée
authors.initials: MR
authors.lastname: Blanchet
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QuébecQC, Canada; Faculty of Medicine, Université Laval, QuébecQC, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Laplante
authors.affiliation: Faculty of Medicine, Université Laval, QuébecQC, Canada; Division of Infectious Diseases and Immunology, CHU de Québec Research Center, QuébecQC, Canada.
authors.forename: Sylvain G
authors.initials: SG
authors.lastname: Bourgoin
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QuébecQC, Canada; Faculty of Medicine, Université Laval, QuébecQC, Canada.
authors.forename: Ynuk
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QuébecQC, Canada; Faculty of Medicine, Université Laval, QuébecQC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Marsolais
keywords: airway hyperresponsiveness; airway smooth muscle; asthma; proliferation; sphingosine analog; sphingosine-1-phosphate