Linoleic acid metabolite drives severe asthma by causing airway epithelial injury

Sci Rep. 2013;3:1349. doi: 10.1038/srep01349.

Abstract

Airway epithelial injury is the hallmark of various respiratory diseases, but its mechanisms remain poorly understood. While 13-S-hydroxyoctadecadienoic acid (13-S-HODE) is produced in high concentration during mitochondrial degradation in reticulocytes little is known about its role in asthma pathogenesis. Here, we show that extracellular 13-S-HODE induces mitochondrial dysfunction and airway epithelial apoptosis. This is associated with features of severe airway obstruction, lung remodeling, increase in epithelial stress related proinflammatory cytokines and drastic airway neutrophilia in mouse. Further, 13-S-HODE induced features are attenuated by inhibiting Transient Receptor Potential Cation Channel, Vanilloid-type 1 (TRPV1) both in mouse model and human bronchial epithelial cells. These findings are relevant to human asthma, as 13-S-HODE levels are increased in human asthmatic airways. Blocking of 13-S-HODE activity or disruption of TRPV1 activity attenuated airway injury and asthma mimicking features in murine allergic airway inflammation. These findings indicate that 13-S-HODE induces mitochondrial dysfunction and airway epithelial injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / genetics
  • Asthma / immunology
  • Asthma / metabolism*
  • Calcium / metabolism
  • Disease Models, Animal
  • Extracellular Space / metabolism
  • Fatty Acids, Unsaturated / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Linoleic Acid / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Neutrophils / immunology
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / pathology*
  • Species Specificity
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism

Substances

  • Fatty Acids, Unsaturated
  • TRPV Cation Channels
  • Linoleic Acid
  • Calcium