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

Abstract

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.

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“…Table 3). Prior studies from our laboratory have demonstrated elevated p-NF-kB in HODE induced steroid resistance in mice (11).…”

“…It was also observed that HODE treated human bronchial epithelia had reduced GRα transcript levels and activity. Further, NF-κB was observed to be partially involved in HODE mediated steroid resistance in mice (11). In the present study, we investigated the plausible mechanism of steroid resistance using HODE treatment in a mice model of asthma.…”

“…In addition, the increase of 13-S-HODE in BAL fluids, sputum and lungs of asthmatic patients is well known (9,10). In this context, our lab has shown recently that the administration of 13-S-HODE to mice with allergic airway inflammation (AAI) led to steroid insensitive asthma like features with neutrophilia (11).…”

“…Administration of 13-S-HODE, Dexamethasone, RXRγ siRNA, RXRγ plasmid, DHA, and ATRA 13-S-HODE (Cayman, Michigan, USA) or VEH (50% ethanol) was instilled into the nasal openings of each isoflurane anesthetized mouse (Models I and VI). Based on our previous publication (11) we have selected the dose of 0.6mg/kg for each mouse. 13-S-HODE was administered intranasally on days 24, 26 and 28 as shown in Figure S5A.…”

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“…For example, the activation state of the transcription factor, nuclear factor kappa-B (NF-κB) is linked to adiponectin [43] and resistin [44], among others [45]. Further to this, NF-κB has been implicated in a number of conditions including cognitive decline, asthma [46], a number of cancers and chemotherapy response. As such, manipulating adipose-secreted factors offers opportunity to develop new treatment strategies [47]; yet the therapeutic potential of these factors has not yet come to fruition and the complexity of adipose tissue is still increasing.…”