Linoleic acid metabolite drives severe asthma by causing airway epithelial injury

Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, India.
Scientific Reports (Impact Factor: 5.58). 02/2013; 3:1349. DOI: 10.1038/srep01349
Source: PubMed


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.

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    • "This confirms recent hypothesis that suggested the central role of airway epithelia in asthma pathogenesis [50, 51]. Very recently, we have demonstrated that 15-LOX and its metabolites cause mitochondrial dysfunction in airway epithelia and drive severe asthmatic conditions in mice [28, 29]. This is interesting as 15-LOX and its metabolites have been shown to be crucial in metabolic syndrome [52–54]. "
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    ABSTRACT: Studying ultrastructural changes could reveal novel pathophysiology of obese-asthmatic condition as existing concepts in asthma pathogenesis are based on the histological changes of the diseased airway. While asthma is defined in functional terms, the potential of electron microscopy (EM) in providing cellular and subcellular detail is underutilized. With this view, we have performed transmission EM in the lungs from allergic mice that show key features of asthma and high-fat- or high-fructose-fed mice that mimicked metabolic syndrome to illustrate the ultrastructural changes. The primary focus was epithelial injury and metaplasia, which are cardinal features of asthma and initiate airway remodeling. EM findings of the allergically inflamed mouse lungs correlate with known features of human asthma such as increased mitochondria in airway smooth muscle, platelet activation and subepithelial myofibroblasts. Interestingly, we found a clear and unambiguous evidence to suggest that ciliated cells can become goblet cells using immunoelectron microscopy. Additionally, we show for the first time the stressed mitochondria in the bronchial epithelia of high-fat- or high-fructose-fed mice even without allergen exposure. These results may stimulate interest in using EM in understanding novel pathological mechanisms for different subtypes of asthma including obese asthma.
    Full-text · Article · Sep 2013
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    • "However, the causal role of mitochondria in the risk factors associated with the features of metabolic syndrome remains to be explored. On the other hand, the involvement of mitochondria in asthma pathogenesis is relatively new and has not been explored in details [25, 42, 77–84]. Obese-asthma, a distinct clinical phenotype of asthma, has been characterized with the presence of neutrophilic airway inflammation, nonatopic nature, low-grade systemic inflammation, increased morbidity, and being resistant to corticosteroids [91–99]. "
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    ABSTRACT: Though severe or refractory asthma merely affects less than 10% of asthma population, it consumes significant health resources and contributes significant morbidity and mortality. Severe asthma does not fell in the routine definition of asthma and requires alternative treatment strategies. It has been observed that asthma severity increases with higher body mass index. The obese-asthmatics, in general, have the features of metabolic syndrome and are progressively causing a significant burden for both developed and developing countries thanks to the westernization of the world. As most of the features of metabolic syndrome seem to be originated from central obesity, the underlying mechanisms for metabolic syndrome could help us to understand the pathobiology of obese-asthma condition. While mitochondrial dysfunction is the common factor for most of the risk factors of metabolic syndrome, such as central obesity, dyslipidemia, hypertension, insulin resistance, and type 2 diabetes, the involvement of mitochondria in obese-asthma pathogenesis seems to be important as mitochondrial dysfunction has recently been shown to be involved in airway epithelial injury and asthma pathogenesis. This review discusses current understanding of the overlapping features between metabolic syndrome and asthma in relation to mitochondrial structural and functional alterations with an aim to uncover mechanisms for obese-asthma.
    Full-text · Article · Jun 2013 · Journal of Allergy
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    • "Briefly, lung cytosolic proteins were separated with SDS-PAGE electrophoresis, transferred to PVDF membranes those were blocked and incubated with 12/15-LOX (Santa Cruz, USA) or α-tubulin (Sigma, St. Louis, MO, USA) antibody followed by respective HRP conjugated secondary antibodies (Sigma, St. Louis, MO, USA) and the membranes were developed with DAB-H2O2 system (Sigma, St. Louis, MO, USA). Immunohistochemical analysis31 for 12/15-LOX was performed with 12/15-LOX and respective HRP conjugated secondary antibody (Sigma, St. Louis, MO, USA). Briefly, 5-μm paraffin embedded lung sections were rehydrated, endogenous peroxidase was eliminated, incubated with 12/15-LOX antibody followed by HRP conjugated secondary antibody and developed with DAB system (Sigma, St. Louis, MO, USA). "
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    ABSTRACT: The mechanisms underlying asthmatic airway epithelial injury are not clear. 12/15-lipoxygenase (an ortholog of human 15-LOX-1), which is induced by IL-13, is associated with mitochondrial degradation in reticulocytes at physiological conditions. In this study, we showed that 12/15-LOX expressed in nonepithelial cells caused epithelial injury in asthma pathogenesis. While 12/15-LOX overexpression or IL-13 administration to naïve mice showed airway epithelial injury, 12/15-LOX knockout/knockdown in allergic mice reduced airway epithelial injury. The constitutive expression of 15-LOX-1 in bronchial epithelia of normal human lungs further indicated that epithelial 15-LOX-1 may not cause epithelial injury. 12/15-LOX expression is increased in various inflammatory cells in allergic mice. Though non-epithelial cells such as macrophages or fibroblasts released 12/15-LOX metabolites upon IL-13 induction, bronchial epithelia didn't release. Further 12-S-HETE, arachidonic acid metabolite of 12/15-LOX leads to epithelial injury. These findings suggested 12/15-LOX expressed in non-epithelial cells such as macrophages and fibroblasts leads to bronchial epithelial injury.
    Full-text · Article · Mar 2013 · Scientific Reports
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