Increasing Sphingolipid Synthesis Alleviates Airway Hyperreactivity

Am J Respir Cell Mol Biol. 2020 Nov;63(5):690-698. doi: 10.1165/rcmb.2020-0194OC.

Abstract

Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity (AHR). The objective was to investigate whether sphingolipid synthesis could be a target for asthma therapeutics. The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on AHR was evaluated in mice deficient in SPT (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. GlyH-101 and fenretinide increased sphinganine and dihydroceramides (de novo sphingolipid metabolites) in lung epithelial and airway smooth-muscle cells, decreased the intracellular calcium concentration in airway smooth-muscle cells, and decreased agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased AHR in SPT-deficient mice in vivo. This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate AHR.

Keywords: asthma; de novo synthesis; smooth muscle; sphingolipid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / metabolism
  • Bradykinin / pharmacology
  • Bronchial Hyperreactivity / metabolism*
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Fenretinide / pharmacology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Humans
  • Hydrazines / pharmacology
  • Metabolome / drug effects
  • Methacholine Chloride / pharmacology
  • Muscle Contraction / drug effects
  • Serine C-Palmitoyltransferase / metabolism
  • Sphingolipids / biosynthesis*

Substances

  • Hydrazines
  • N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide
  • Sphingolipids
  • Methacholine Chloride
  • Fenretinide
  • Serine C-Palmitoyltransferase
  • Bradykinin
  • Calcium
  • Glycine