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A1292 - Biphasic Responses of Sphingolipids in Airway Inflammation and Airway Hyperreactivity
Author Block: J. L. Sturgill1, C. Oyeniran2, A. Montpetit3, S. Milstien2, S. Spiegel2; 1Internal Medicine - Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, KY, United States, 2Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, United States, 3Department of Emergency Medicine, Virginia Commonwealth University, Richmond, VA, United States.
Rationale: Asthma, defined as a chronic inflammatory condition characterized by episodic shortness of breath with expiratory wheezing and cough, is a serious health concern. The WHO estimates that asthma affects more than 230 million people worldwide. There is a strong genetic component to asthma and numerous genome-wide association studies have identified ORM (yeast)-like protein isoform 3 (ORMDL3) as an asthma associated gene. Surprisingly however, the mechanism by which ORMDL3 contributes to asthma pathogenesis is not well understood. The yeast ortholog of ORMDL3 is a negative regulator of serine palmitoyltransferase (SPT), the rate limiting step in de novo sphingolipid synthesis, yet elevations of sphingolipids rather than reductions have been linked to lung inflammation. Thus, our laboratory is examining the role of ORMDL3 and sphingolipids in asthma immunopathology in terms of airway inflammation and airway hyperreactivity (AHR). Methods: We used murine models of allergic lung inflammation including papain, Alternaria alternata, and house dust mite. Administration of the orally available FDA approved prodrug FTY720/fingolimod, the ceramide synthase inhibitor, fumonisin B1, or SPT inhibitor myriocin were used throughout the course of challenge to determine efficacy of sphingolipid blockade. Results: We observe a significant increase in sphingolipids post allergen challenge in both the BALF and lung tissue of mice. We also see corresponding increases in inflammatory cell infiltration, mucus hypersecretion, and AHR. We found a surprising role for the sphingolipid metabolite, sphingosine 1 phosphate (S1P), for airway inflammation, especially in early, innate events. Exciting preliminary data suggest that S1P may specifically be important in the development of allergic airway disease. We also found that ceramide levels strongly correlate with AHR and that reductions in ceramide have significant effects of AHR. Conclusion: These data highlight an important and emerging role of sphingolipids in pulmonary biology and that pharmacologic targeting of this pathway may be beneficial for the control of asthma. Blocking these lipid mediators may open the door for novel, steroid sparing therapeutics, especially for the control of AHR.