title: Cys-leukotrienes promote fibrosis in a mouse model of eosinophil-mediated respiratory inflammation.
abstract: Leukotrienes (i.e., products of the 5-lipoxygenase pathway) are thought to be contributors to lung pathologies. Moreover, eosinophils have been linked with pulmonary leukotriene activities both as potential sources of these mediators and as responding effector cells. The objective of the present study was to define the role(s) of leukotrienes in the lung pathologies accompanying eosinophil-associated chronic respiratory inflammation. A transgenic mouse model of chronic T helper (Th) 2-driven inflammation expressing IL-5 from T cells and human eotaxin-2 locally in the lung (I5/hE2) was used to define potential in vivo relationships among eosinophils, leukotrienes, and chronic Th2-polarized pulmonary inflammation. Airway levels of cys-leukotrienes and leukotriene B4 (LTB4) are both significantly elevated in I5/hE2 mice. The eosinophil-mediated airway hyperresponsiveness (AHR) characteristic of these mice was abolished in the absence of leukotrienes (i.e., 5-lipoxygenase-deficient I5/hE2). More importantly, the loss of leukotrienes led to an unexpectedly significant decrease in collagen deposition (i.e., pulmonary fibrosis) that accompanied elevated levels of IL-4/-13 and TGF-β in the lungs of I5/hE2 mice. Further studies using mice deficient for the LTB4 receptor (BLT-1(-/-)/I5/hE2) and I5/hE2 animals administered a cys-leukotriene receptor antagonist (montelukast) demonstrated that the AHR and the enhanced pulmonary fibrosis characteristic of the I5/hE2 model were uniquely cys-leukotriene-mediated events. These data demonstrate that, similar to allergen challenge models of wild-type mice, cys-leukotrienes underlie AHR in this transgenic model of severe pulmonary Th2 inflammation. These data also suggest that an underappreciated link exists among eosinophils, cys-leukotriene-mediated events, and fibrotic remodeling associated with elevated levels of IL-4/-13 and TGF-β.
authors.affiliation: 1 Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona.
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Ochkur
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Protheroe
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Dana C
authors.initials: DC
authors.lastname: Colbert
authors.forename: Katie R
authors.initials: KR
authors.lastname: Zellner
authors.forename: Hua-Hao
authors.initials: HH
authors.lastname: Shen
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Lee
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000276:immunology; D054423:Chemokine CCL24 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology* / Q000473:pathology; D006801:Humans; D015848:Interleukin-5 / Q000276:immunology; D007975:Leukotriene B4 / Q000276:immunology; D015289:Leukotrienes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011014:Pneumonia / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D018102:Receptors, Leukotriene B4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
chemical_list: C515484:CCL24 protein, human; D054423:Chemokine CCL24; D015848:Interleukin-5; D015289:Leukotrienes; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase