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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / blood
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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / immunology
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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / metabolism
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3T3 Cells
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Animals
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Arachidonate 12-Lipoxygenase / genetics
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Arachidonate 12-Lipoxygenase / immunology*
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Arachidonate 12-Lipoxygenase / metabolism
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Arachidonate 15-Lipoxygenase / genetics
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Arachidonate 15-Lipoxygenase / immunology*
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Arachidonate 15-Lipoxygenase / metabolism
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Asthma / genetics
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Asthma / immunology*
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Asthma / metabolism
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Blotting, Western
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Cell Line
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Cytochromes c / immunology
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Cytochromes c / metabolism
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Epithelium / drug effects
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Epithelium / immunology
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Epithelium / pathology
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Fibroblasts / drug effects
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Fibroblasts / immunology*
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Fibroblasts / metabolism
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Humans
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Immunohistochemistry
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Interleukin-13 / administration & dosage
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Interleukin-13 / immunology
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Interleukin-13 / pharmacology
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Lactones
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Linoleic Acids / blood
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Linoleic Acids / immunology
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Linoleic Acids / metabolism
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Lung / immunology
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Lung / metabolism
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Lung / ultrastructure
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Macrophages / drug effects
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Macrophages / immunology*
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Macrophages / metabolism
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Male
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Membrane Potential, Mitochondrial / drug effects
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Membrane Potential, Mitochondrial / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Electron, Transmission
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Mitochondria / immunology
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Mitochondria / metabolism
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Mitochondria / physiology
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Sesquiterpenes, Eudesmane
Substances
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12-15-lipoxygenase
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13-sulfo-dihydroreynosin
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Interleukin-13
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Lactones
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Linoleic Acids
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Sesquiterpenes, Eudesmane
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13-hydroxy-9,11-octadecadienoic acid
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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
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Cytochromes c
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Arachidonate 12-Lipoxygenase
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Arachidonate 15-Lipoxygenase