Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB

Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. I...

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Published in:Scientific reports 2017-08, Vol.7 (1), p.9565-11, Article 9565
Main Authors: Panda, Lipsa, Gheware, Atish, Rehman, Rakhshinda, Yadav, Manish K, Jayaraj, B S, Madhunapantula, SubbaRao V, Mahesh, Padukudru Anand, Ghosh, Balaram, Agrawal, Anurag, Mabalirajan, Ulaganathan
Format: Article
Language:English
Subjects:
Airway management
Animal models
Animals
Anti-Asthmatic Agents - pharmacology
Asthma
Asthma - drug therapy
Asthma - metabolism
Asthma - pathology
Dexamethasone
Disease Models, Animal
Drug Resistance
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Glucocorticoids
High fat diet
Humans
Hypersensitivity - drug therapy
Hypersensitivity - immunology
Hypersensitivity - metabolism
Hypersensitivity - pathology
Inflammation
Leukocytes (neutrophilic)
Linoleic acid
Linoleic Acid - metabolism
Lipid Metabolism
Lipoxygenase
Metaplasia
Mice
Mitochondria
NF-kappa B - metabolism
NF-κB protein
Receptors, Glucocorticoid - metabolism
Respiratory Mucosa - drug effects
Respiratory Mucosa - metabolism
Respiratory Mucosa - pathology
Respiratory tract
Respiratory tract diseases
Rodents
Steroids - pharmacology
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Summary:Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15-lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-09869-9