Increasing Sphingolipid Synthesis Alleviates Airway Hyperreactivity.

RATIONALE: Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity.

OBJECTIVES: To investigate if sphingolipid synthesis could be a target for asthma therapeutics.

METHODS: The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on airway hyperreactivity was evaluated in mice deficient in serine palmitoyl-CoA transferase, the rate limiting enzyme of sphingolipid synthesis. The drugs were also used directly in human airway smooth muscle and epithelial cells to evaluate changes in de novo sphingolipid metabolites and calcium release.

RESULTS: GlyH-101 and fenretinide increased sphinganine and dihydroceramides (de novo sphingolipid metabolites) in lung epithelial and airway smooth muscle cells, decrease intracellular calcium concentration in airway smooth muscle cells, and decrease agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased airway hyperreactivity in SPT-deficient mice in vivo.

CONCLUSIONS: This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate airway hyperreactivity.

https://www.ncbi.nlm.nih.gov/pubmed/32706610?dopt=Abstract