Eliminating or blocking 12/15-lipoxygenase reduces neutrophil recruitment in mouse models of acute lung injury

Critical Care

Alexander Zarbock³  Klaus Ley²  Jerry L Nadler¹  Jan Rossaint³ 

[1] Department of Internal Medicine, Eastern Virginia Medical School, P.O. Box 1980, Norfolk, VA 23501-1980, USA;Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA;Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, Münster, 48149, Germany

关键词: leukocyte recruitment;    inflammation;    acute lung injury;    lipoxygenase;   

Others  :  825976
DOI  :  10.1186/cc11518

 received in 2012-04-09, accepted in 2012-09-13,  发布年份 2012

【 摘 要 】

Introduction

Acute lung injury (ALI) is a common disease in critically ill patients with a high morbidity and mortality. 12/15-lipoxygenase (12/15-LO) is an enzyme generating 12-hydroxy-eicosatetraenoic acid (12-HETE) and 15-HETE from arachidonic acid. It has been shown that 12/15-LO is involved in the regulation of vascular permeability during ALI.

Methods

To test whether 12/15-LO participates in leukocyte recruitment into the lung, we investigated the role of 12/15-LO in mouse models of lipopolysaccharide (LPS)-induced pulmonary inflammation and acid-induced ALI, a clinically relevant model of acute lung injury.

Results

The increase in neutrophil recruitment following LPS inhalation was reduced in 12/15-LO-deficient (Alox15^-/-) mice and in wild-type (WT) mice after the blocking of 12/15-LO with a pharmacological inhibitor. Bone marrow chimeras revealed that 12/15-LO in hematopoietic cells regulates neutrophil accumulation in the interstitial and alveolar compartments, whereas the accumulation of neutrophils in the intravascular compartment is regulated by 12/15-LO in non-hematopoietic and hematopoietic cells. Mechanistically, the increased plasma levels of the chemokine CXCL1 in Alox15^-/- mice led to a reduced response of the neutrophil chemokine receptor CXCR2 to stimulation with CXCL1, which in turn abrogated neutrophil recruitment. Alox15^-/- mice also showed decreased edema formation, reduced neutrophil recruitment and improved gas exchange in an acid-induced ALI model.

Conclusions

Our findings suggest that 12/15-LO modulates neutrophil recruitment into the lung by regulating chemokine/chemokine receptor homeostasis.

【 授权许可】

   
2012 Rossaint et al.; licensee BioMed Central Ltd.

【 图 表 】

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