title: Airway reactivity and sphingolipids-implications for childhood asthma.
abstract: Asthma is a clinically heterogeneous disorder, whose onset and progression results from a complex interplay between genetic susceptibility, allergens, and viral triggers. Sphingolipids and altered sphingolipid metabolism have emerged as potential key contributors to the pathogenesis of asthma. Orosomucoid-like 3 gene (ORMDL3) and the asthma susceptibility locus 17q21 have been strongly and reproducibly linked to childhood asthma, but how this gene is functionally linked to asthma is incompletely understood. ORMDL proteins play an integral role in sphingolipid homeostasis and synthesis, and asthma-associated ORMDL3 polymorphisms have been associated with early viral respiratory infections and increased risk of asthma. ORMDL proteins act as inhibitors of serine palmitoyl-CoA transferase (SPT), the rate-limiting enzyme for de novo sphingolipid synthesis, and decreased sphingolipid synthesis through SPT increases airway hyperreactivity, which is independent of allergy or inflammation. In allergic models of asthma, the sphingolipid mediators sphingosine-1-phosphate (S1P) and ceramide have been shown to be important signaling molecules for airway hyperreactivity, mast cell activation, and inflammation. This review will highlight how sphingolipids and altered sphingolipid metabolism may contribute towards the underlying mechanisms of childhood asthma.
authors.affiliation: Department of Pediatrics, Weill Cornell Medical College, 505 East 70th Street, Box 211, New York, NY, 10021, USA.
authors.forename: Jennie G
authors.initials: JG
authors.lastname: Ono
authors.affiliation: Department of Pathology, Columbia University, New York, NY, USA.
authors.forename: Tilla S
authors.initials: TS
authors.lastname: Worgall
authors.affiliation: Department of Pediatrics, Weill Cornell Medical College, 505 East 70th Street, Box 211, New York, NY, 10021, USA. stw2006@med.cornell.edu.|Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA. stw2006@med.cornell.edu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Worgall
keywords: Airway hyperreactivity; Asthma; ORMDL3; Rhinovirus; SPT; Sphingolipids