Abstract
Acute lung injury (ALI) is a prevalent disease associated with high mortality. 12/15-lipoxygenase (12/15-LO) is an enzyme producing 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE from arachidonic acid. To test whether 12/15-LO is involved in increasing vascular permeability in the lung, we investigated the role of 12/15-LO in murine models of LPS-induced pulmonary inflammation and clinically relevant acid-induced ALI. The vascular permeability increase upon LPS inhalation was abolished in Alox15(-/-) mice lacking 12/15-LO and in wild-type mice after pharmacological blockade of 12/15-LO. Alox15(-/-) mice also showed improved gas exchange, reduced permeability increase, and prolonged survival in the acid-induced ALI model. Bone marrow chimeras and reconstitution experiments revealed that 12-HETE produced by hematopoietic cells regulates vascular permeability through a CXCR2-dependent mechanism. Our findings suggest that 12/15-LO-derived 12-HETE is a key mediator of vascular permeability in acute lung injury.
Publication types
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Research Support, N.I.H., Extramural
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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 / physiology
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Acute Lung Injury / enzymology*
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Acute Lung Injury / immunology
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Acute Lung Injury / mortality*
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Acute Lung Injury / pathology
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Animals
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Arachidonate 12-Lipoxygenase / deficiency*
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Arachidonate 12-Lipoxygenase / genetics
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Arachidonate 15-Lipoxygenase / deficiency*
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Arachidonate 15-Lipoxygenase / genetics
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Caffeic Acids / administration & dosage
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Capillary Permeability / genetics
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Capillary Permeability / immunology*
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Cells, Cultured
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Disease Models, Animal
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Humans
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Inflammation Mediators / administration & dosage
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Lipopolysaccharides / administration & dosage
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Lipoxygenase Inhibitors*
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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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Microcirculation / genetics
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Microcirculation / immunology
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Multienzyme Complexes / antagonists & inhibitors*
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Multienzyme Complexes / deficiency*
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Multienzyme Complexes / genetics
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Survival Analysis
Substances
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Caffeic Acids
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Inflammation Mediators
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Lipopolysaccharides
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Lipoxygenase Inhibitors
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Multienzyme Complexes
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cinnamyl-3,4-dihydroxycyanocinnamate
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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
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Alox15 protein, mouse
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Arachidonate 12-Lipoxygenase
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Arachidonate 15-Lipoxygenase