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.
|
Authors | Alexander Zarbock, Matthew R Distasi, Emily Smith, John M Sanders, Gerhard Kronke, Brian L Harry, Sibylle von Vietinghoff, Konrad Buscher, Jerry L Nadler, Klaus Ley |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 183
Issue 7
Pg. 4715-22
(Oct 01 2009)
ISSN: 1550-6606 [Electronic] United States |
PMID | 19752233
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Caffeic Acids
- Inflammation Mediators
- Lipopolysaccharides
- Lipoxygenase Inhibitors
- Multienzyme Complexes
- cinnamyl-3,4-dihydroxycyanocinnamate
- 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
- Alox15 protein, mouse
- Arachidonate 12-Lipoxygenase
- Arachidonate 15-Lipoxygenase
|
Topics |
- 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
(physiology)
- Acute Lung Injury
(enzymology, immunology, mortality, pathology)
- Animals
- Arachidonate 12-Lipoxygenase
(deficiency, genetics)
- Arachidonate 15-Lipoxygenase
(deficiency, genetics)
- Caffeic Acids
(administration & dosage)
- Capillary Permeability
(genetics, immunology)
- Cells, Cultured
- Disease Models, Animal
- Humans
- Inflammation Mediators
(administration & dosage)
- Lipopolysaccharides
(administration & dosage)
- Lipoxygenase Inhibitors
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Microcirculation
(genetics, immunology)
- Multienzyme Complexes
(antagonists & inhibitors, deficiency, genetics)
- Survival Analysis
|