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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)¹

Alexander Zarbock^2,*,,, Matthew R. DiStasi, Emily Smith^*, John M. Sanders^*, Gerhard Kronke^*, Brian L. Harry^*, Sibylle von Vietinghoff, Konrad Buscher, Jerry L. Nadler^*, and Klaus Ley^*,

^* Robert M. Berne Cardiovascular Research Center and Internal Medicine, University of Virginia, Charlottesville, VA 22908; Department of Anesthesiology and Intensive Care Medicine, University of Münster, Münster, Germany; and La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by Else Kröner-Fresenius-Stiftung (Grant A69/07 to A.Z.), by the German Research Foundation (ZA428/2-1 to A.Z., VI508/1-1 to S.v.V.), by National Institutes of Health Grant P01 HL 73361 to Joel Linden (project 2 to K.L.), and by National Institutes of Health Grant P01 HL 55798 to J.N. (project 4 to K.L.).

² Address correspondence and reprint requests to Dr. Alexander Zarbock, Department of Anesthesiology and Critical Care Medicine, University of Muenster, Albert-Schweitzer Strasse 33, 48149 Muenster, Germany. E-mail address: zarbock{at}uni-muenster.de

³ Abbreviations used in this paper: ALI, acute lung injury; BAL, bronchoalveolar lavage; CDC, cinnamyl-3,4-dihydroxy--cyanocinnamate; FiO₂, fraction of inspiratory oxygen; HETE, hydroxyeicosatetraenoic acid; LO, lipoxygenase; PaO₂, partial pressure of arterial oxygen; WT, wild type.