The Study of Sphingolipid Metabolism in Airway Remodeling

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We have examined the function of sphingosine 1-phospate (S1P), one of strong lipid inflammatory mediators, in the mechanism of bronchial asthma. To understand the role of sphingplipids, we designed in vitro and in vivo studies as below. However, our plans have not completed yet and some projects have been still undergoing.1)The analysis of sphingolipid function in bronchial epithelial cells and lung fibroblastsRecent article revealed that S1P is increased in bronchoalveolar lavage fluid of asthma patients after antigen challenge. To clarify the function of increased S1P, we studied the activity of sphingosine kinases that produce S1P in bronchial epithelial cells. TNFα stimulation increased the activities of both two isoforms of sphingosine kinase, whereas S1P itself attracted MMP and IL-8 secretion (in submission data). Moreover, we showed that S1P induced myofibroblast formation in lung fibroblasts via a Rho-dependent pathway, as well as TGFβ (in submission data). We concluded that sphingolipids is one of key factors for airway remodeling, then gene introduction of sphingosine kinases into cultured cells is preparing.2)The analysis of sphingosine kinase expression in ovalbumin(OVA)-sensitized miceC57/BL6 mice received OVA inhalation for 3 to 21 consecutive days after sensitization. We compared two strategies of acute and chronic phases. Western blot analysis and real time PCR revealed that sphingosine kinase expression was decreased temporary at 3-day inhalation and recovered at 21-day (unpublished data). Immunohistochemical study has been undergoing and we are preparing in vivo gene introduction study of sphingosine kinases for further analysis.