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* Department of Physiology and
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
Asthma is an allergic disease characterized by chronic airway eosinophilia and pulmonary infiltration of lymphocytes, particularly of the Th2 subtype, macrophages and mast cells. Previous studies have shown a pivotal role for sphingosine kinase (SphK) on various proinflammatory cells, such as lymphocyte and eosinophil migration and mast cell degranulation. We therefore examined the roles of SphK in a murine model of allergic asthma. In mice previously sensitized to OVA, i.p. administration of N,N-dimethylsphingosine (DMS), a potent SphK inhibitor, significantly reduced the total inflammatory cell infiltrate and eosinophilia and the IL-4, IL-5, and eotaxin levels in bronchoalveolar lavage fluid in response to inhaled OVA challenge. In addition, DMS significantly suppressed OVA-induced inflammatory infiltrates and mucus production in the lungs, and airway hyperresponsiveness to methacholine in a dose-dependent manner. OVA-induced lymphocyte proliferation and IL-4 and IL-5 secretion were reduced in thoracic lymph node cultures from DMS-treated mice. Moreover, similar reduction in inflammatory infiltrates, bronchoalveolar lavage, IL-4, IL-5, eotaxin, and serum OVA-specific IgE levels was observed in mice with SphK1 knock-down via small interfering RNA approach. Together, these data demonstrate the therapeutic potential of SphK modulation in allergic airways disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Office of Life Sciences, National University of Singapore. W.-Q.L. is supported by a scholarship from the National University of Singapore, Republic of Singapore.
2 W.-Q.L. and H.H.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Bernard P. Leung, Department of Physiology, 2 Medical Drive, MD9, National University of Singapore, Singapore 117597, Republic of Singapore. E-mail address: phslplb{at}nus.edu.sg
4 Abbreviations used in this paper: S1P, sphingosine 1-phosphate; AHR, airway hyperresponsiveness; i.n., intranasally; BAL, bronchoalveolar lavage; DMS, N,N-dimethylsphingosine; siRNA, small interfering RNA; SphK, sphingosine kinase; PAS, periodic acid-Schiff; RL, pulmonary resistance; Cdyn, dynamic compliance; ASM, airway smooth muscle.
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