Improved survival and reduced vascular permeability by eliminating or blocking 12/15-lipoxygenase in mouse models of acute lung injury (ALI).
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.
Zarbock
Alexander
A
Robert M. Berne Cardiovascular Research Center, Department of Anesthesiology and Critical Care Medicine, University of Muenster, Albert-Schweitzer Strasse 33, Muenster 48149, Germany. zarbock@uni-muenster.de
Distasi
Matthew R
MR
Smith
Emily
E
Sanders
John M
JM
Kronke
Gerhard
G
Harry
Brian L
BL
von Vietinghoff
Sibylle
S
Buscher
Konrad
K
Nadler
Jerry L
JL
Ley
Klaus
K
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000502:physiology; D055371:Acute Lung Injury / Q000201:enzymology* / Q000276:immunology / Q000401:mortality* / Q000473:pathology; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D002109:Caffeic Acids / Q000008:administration & dosage; D002199:Capillary Permeability / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage; D008070:Lipopolysaccharides / Q000008:administration & dosage; D016859:Lipoxygenase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000235:genetics / Q000276:immunology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D016019:Survival Analysis
D002109:Caffeic Acids; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D009097:Multienzyme Complexes; C099255:cinnamyl-3,4-dihydroxycyanocinnamate; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase