title: Eliminating or blocking 12/15-lipoxygenase reduces neutrophil recruitment in mouse models of acute lung injury.
abstract: BACKGROUND
  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.
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*
chemical_list: C475064:12-15-lipoxygenase; D004791:Enzyme Inhibitors; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase