Inhibition of Sphingolipid Synthesis Produced Asthmatic Lungs, without Inflammation eInterview with: Stefan Worgall Ph.D., M.D

Department of Genetic Medicine and 4Department of Pediatrics
Weill Cornell Medical College,
New York, NY 10021, USA. What are the main findings of the study?

Dr. Worgall: Asthma is a common disease and large genome-wide association studies  found variation in the gene for ORMDL3, in to up to 30 percent of asthma cases. The over-production ORMDL3 was connected to childhood asthma. ORMDL3 protein inhibits the new production of sphingolipids. Our study connects sphingolipid metabolism mechanistically to human asthma for the first time. We found that inhibition of the enzyme that is critical to sphingolipid synthesis, serine palmitoyl-CoA transferase (SPT),  produced asthmatic lungs in mice and in human bronchi, as it did in mice that had a genetic defect in SPT. When these mice were given methacholine their airways constricted further. We further determined that the airway hyperactivity seen in the mice was not linked to increased inflammation, which is a target for most asthma therapies.

We saw a decreased response of the lung and airways to magnesium. Giving magnesium to the mice did not relax their lung contractions, suggesting the same would be true for humans whose asthma is linked to ORMDL3. Our findings find, for the first time, a mechanism how ORMDL3 connects to asthma and identifies sphingolipid production to be important for bronchial constriction, an important characteristic of all asthma types. Were any of the findings unexpected?

Dr. Worgall: To observe such a strong effect of decreased sphinolipid synthesis, even after a few hours, on airway reactivity was surprising. Also unexpected was that there was no inflammation observed in both models. What should clinicians and patients take away from your report?

Dr. Worgall: Asthma has various types and some of these types may responsive to therapies that alter sphingolipids. What recommendations do you have for future research as a result of this study?

Future research needs to evaluate if changing the sphingolipid synthesis pathway could be used for novel asthma therapies. It might be possible to design agents that activate the SPT enzyme in lung tissue, increasing production of sphingolipids.


Impaired sphingolipid synthesis in the respiratory tract induces airway hyperreactivity

Worgall TS, Veerappan A, Sung B, Kim BI, Weiner E, Bholah R, Silver RB, Jiang XC, Worgall S.

Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
Sci Transl Med. 2013 May 22;5(186):186ra67.