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Improved survival and reduced vascular permeability by eliminating or blocking 12/15-lipoxygenase in mouse models of acute lung injury (ALI).

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.
AuthorsAlexander Zarbock, Matthew R Distasi, Emily Smith, John M Sanders, Gerhard Kronke, Brian L Harry, Sibylle von Vietinghoff, Konrad Buscher, Jerry L Nadler, Klaus Ley
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 7 Pg. 4715-22 (Oct 01 2009) ISSN: 1550-6606 [Electronic] United States
PMID19752233 (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

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