title: The role of sphingosine kinase in a murine model of allergic asthma.
abstract: 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.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Wen-Qi
authors.initials: WQ
authors.lastname: Lai
authors.forename: Hong Heng
authors.initials: HH
authors.lastname: Goh
authors.forename: Zhang
authors.initials: Z
authors.lastname: Bao
authors.forename: W S Fred
authors.initials: WS
authors.lastname: Wong
authors.forename: Alirio J
authors.initials: AJ
authors.lastname: Melendez
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Leung
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000627:therapeutic use; D013110:Sphingosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018418:Th2 Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D000099157:Sphingosine Kinase
chemical_list: D000485:Allergens; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D010047:Ovalbumin; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D013110:Sphingosine; D000099157:Sphingosine Kinase; C061800:N,N-dimethylsphingosine