13-Hydroxy-linoleic acid induces airway hyperresponsiveness to histamine and methacholine in guinea pigs in vivo

Henricks, Paul A.J.; Engels, Ferdi; Lindea, Henk J. van der; Garssen, Johan; Nijkamp, Frans P.

doi:10.1016/s0091-6749(95)70030-7

Cited by 13 publications

(10 citation statements)

References 33 publications

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“…Similarly dysfunctional mitochondria have been found in human asthmatic bronchial epithelia30. Transfer of mitochondria from stem cells to alveolar epithelial cells reversed acute lung injury in sepsis, indicating the crucial role that mitochondrial health in lung diseases17. In this context, understanding the effects of 13-S-HODE on airway epithelium is essential because we found its levels to be high in the airway secretions and extracellular fluids.…”

Section: Discussionsupporting

confidence: 62%

“…13-S-hydroxyoctadecadienoic acid (13-S-HODE) is a lipid metabolite derived from linoleic acid, a major polyunsaturated fatty acid, through various enzymatic sources like 15-lipoxygenase, cyclooxygenase and nonenzymatic mechanisms like auto-oxidation131415. 13-S-HODE is produced in large quantities during mitochondrial degradation steps in RBC maturation16 whereas 13-hydroxy-linoleic acid, a related molecule, has been linked to airway hyperresponsiveness17. We studied 13-S-HODE as a potential link between mitochondrial dysfunction, epithelial injury, and airway disease because of increasing evidence of the role of mitochondrial dysfunction789.…”

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confidence: 99%

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Linoleic acid metabolite drives severe asthma by causing airway epithelial injury

Mabalirajan

Rehman

Ahmad

et al. 2013

Sci Rep

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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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Section: Discussionsupporting

confidence: 62%

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confidence: 99%

Linoleic acid metabolite drives severe asthma by causing airway epithelial injury

Mabalirajan

Rehman

Ahmad

et al. 2013

Sci Rep

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“…Among the significantly altered 15-LOX products, 13-HODE is the most well studied LA derivative and of demonstrated importance in airway disease [33], [37]. 13-HODE has been shown to alter the activity of the anti-inflammatory receptor PPARγ in a concentration dependent manner [33], [38], [39].…”

Section: Discussionmentioning

confidence: 99%

Asthmatics Exhibit Altered Oxylipin Profiles Compared to Healthy Individuals after Subway Air Exposure

et al. 2011

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BackgroundAsthma is a chronic inflammatory lung disease that causes significant morbidity and mortality worldwide. Air pollutants such as particulate matter (PM) and oxidants are important factors in causing exacerbations in asthmatics, and the source and composition of pollutants greatly affects pathological implications.ObjectivesThis randomized crossover study investigated responses of the respiratory system to Stockholm subway air in asthmatics and healthy individuals. Eicosanoids and other oxylipins were quantified in the distal lung to provide a measure of shifts in lipid mediators in association with exposure to subway air relative to ambient air.MethodsSixty-four oxylipins representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of bronchoalveolar lavage (BAL)-fluid. Validations through immunocytochemistry staining of BAL-cells were performed for 15-LOX-1, COX-1, COX-2 and peroxisome proliferator-activated receptor gamma (PPARγ). Multivariate statistics were employed to interrogate acquired oxylipin and immunocytochemistry data in combination with patient clinical information.ResultsAsthmatics and healthy individuals exhibited divergent oxylipin profiles following exposure to ambient and subway air. Significant changes were observed in 8 metabolites of linoleic- and α-linolenic acid synthesized via the 15-LOX pathway, and of the COX product prostaglandin E2 (PGE2). Oxylipin levels were increased in healthy individuals following exposure to subway air, whereas asthmatics evidenced decreases or no change.ConclusionsSeveral of the altered oxylipins have known or suspected bronchoprotective or anti-inflammatory effects, suggesting a possible reduced anti-inflammatory response in asthmatics following exposure to subway air. These observations may have ramifications for sensitive subpopulations in urban areas.

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“…In other words, exogenous PPAR␥ agonists in therapeutic concentrations might act as a negative immunomodulator, whereas endogenous or natural ligands in physiological concentrations might have some proinflammatory effects. It is also worth noting that naturally occurring fatty acid-derived molecules, such as 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, which are also known as ligands of PPAR␥, contribute to the pathophysiology of allergic airway inflammation (38,39). Thus, additional studies are necessary to clarify the physiological role of PPAR␥.…”

mentioning

confidence: 99%

Physiological Levels of 15-Deoxy-Δ12,14-Prostaglandin J2 Prime Eotaxin-Induced Chemotaxis on Human Eosinophils through Peroxisome Proliferator-Activated Receptor-γ Ligation

Kobayashi

Ueki

Mahemuti

et al. 2005

The Journal of Immunology

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15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2), mainly produced by mast cells, is known as a potent lipid mediator derived from PGD2 in vivo. 15d-PGJ2 was thought to exert its effects on cells exclusively through peroxisome proliferator-activated receptor-γ (PPARγ) and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), which are both expressed on human eosinophils. However, the physiological role of 15d-PGJ2 remains unclear, because the concentration generated in vivo is generally much lower than that required for its biological functions. In the present study we found that low concentrations (picomolar to low nanomolar) of 15d-PGJ2 and a synthetic PPARγ agonist markedly enhanced the eosinophil chemotaxis toward eotaxin, and the effect was decreased in a dose-dependent manner. Moreover, at a low concentration (10−10 M), 15d-PGJ2 and troglitazone primed eotaxin-induced shape change and actin polymerization. These priming effects were completely reversed by a specific PPARγ antagonist, but were not mimicked by CRTH2 agonist 13,14-dihydro-15-keto-PGD2, suggesting that the effects were mediated through PPARγ ligation. The effect exerted by 15d-PGJ2 parallels the enhancement of Ca2+ influx, but is not associated with the ERK, p38 MAPK, and NF-κB pathways. Furthermore, the time course and treatment of eosinophils with actinomycin D, an inhibitor of gene transcription, indicated that the transcription-independent pathway had a role in this process. PPARγ might interact with an eotaxin-induced cytosolic signaling pathway, because PPARγ is located in the eosinophil cytosol. Taken together with current findings, these results suggest that under physiological conditions, 15d-PGJ2 contributes to allergic inflammation through PPARγ, which plays a role as a biphasic regulator of immune response.

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13-Hydroxy-linoleic acid induces airway hyperresponsiveness to histamine and methacholine in guinea pigs in vivo

Cited by 13 publications

References 33 publications

Linoleic acid metabolite drives severe asthma by causing airway epithelial injury

Linoleic acid metabolite drives severe asthma by causing airway epithelial injury

Asthmatics Exhibit Altered Oxylipin Profiles Compared to Healthy Individuals after Subway Air Exposure

Physiological Levels of 15-Deoxy-Δ12,14-Prostaglandin J2 Prime Eotaxin-Induced Chemotaxis on Human Eosinophils through Peroxisome Proliferator-Activated Receptor-γ Ligation

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