Abstract
IntroductionAcute 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.MethodsTo 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.ResultsThe 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.ConclusionsOur findings suggest that 12/15-LO modulates neutrophil recruitment into the lung by regulating chemokine/chemokine receptor homeostasis.
Highlights
Acute lung injury (ALI) is a common disease in critically ill patients with a high morbidity and mortality. 12/15-lipoxygenase (12/15-lipoxygenase is expressed in humans and rabbits (15-LO)) is an enzyme generating 12-hydroxy-eicosatetraenoic acid (12-HETE) and 15-hydroxy-eicosatetraenoic acid (15-HETE) from arachidonic acid
We previously demonstrated that 12-HETE, the product of 12/15-LO, produced by hematopoietic cells plays a key role in the regulation of vascular permeability in LPS-induced pulmonary inflammation and acidinduced ALI through a C-X-C motif receptor 2 (CXCR2)-dependent mechanism [31]
To reveal the mechanisms by which 12/15-LO modulates neutrophil recruitment, we investigated the role of 12/15-LO on the chemokine/chemokine receptor homeostasis
Summary
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. Acute lung injury (ALI) is a common disease in critically ill patients with a high morbidity and mortality. It has been shown that 12/15-LO is involved in the regulation of vascular permeability during ALI. Acute lung injury (ALI) is a severe disease with a high incidence [1]. ALI is associated with high mortality despite improved treatment [1], causes 3.6 million hospital days per year, and is a huge burden for the health care system [1]. It has been shown that CXCR2, the chemokine receptor for CXCL1 (keratinocyte-derived chemokine, KC) and CXCL2/3 (macrophage inflammatory protein 2, MIP-2) in the mouse system, is involved in the regulation of vascular permeability and in neutrophil recruitment in different models of ALI [5,6,7]. A recently published study demonstrated that human CXCL8 (interleukin 8; IL-8), a ligand for human CXCR1 and CXCR2 [8] can form complexes with autoantibodies associated with the development and outcome of ALI in patients [9]
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