Cys-leukotrienes promote fibrosis in a mouse model of eosinophil-mediated respiratory inflammation.
| Title: | Cys-leukotrienes promote fibrosis in a mouse model of eosinophil-mediated respiratory inflammation. |
|---|---|
| Authors: | Ochkur SI; 1 Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona.; Protheroe CA; Li W; Colbert DC; Zellner KR; Shen HH; Luster AD; Irvin CG; Lee JJ; Lee NA |
| Source: | American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2013 Dec; Vol. 49 (6), pp. 1074-84. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Thoracic Society Country of Publication: United States NLM ID: 8917225 Publication Model: Print Cited Medium: Internet ISSN: 1535-4989 (Electronic) Linking ISSN: 10441549 NLM ISO Abbreviation: Am J Respir Cell Mol Biol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2000- : New York, NY : American Thoracic Society; Original Publication: [New York, NY : The Association, [c1989- |
| MeSH Terms: | Eosinophils/*immunology ; Leukotrienes/*immunology ; Pneumonia/*etiology ; Pulmonary Fibrosis/*etiology; Arachidonate 5-Lipoxygenase/deficiency ; Arachidonate 5-Lipoxygenase/genetics ; Arachidonate 5-Lipoxygenase/immunology ; Bronchial Hyperreactivity/immunology ; Chemokine CCL24/genetics ; Chemokine CCL24/immunology ; Eosinophils/pathology ; Interleukin-5/immunology ; Leukotriene B4/immunology ; Pneumonia/immunology ; Pneumonia/pathology ; Pulmonary Fibrosis/immunology ; Pulmonary Fibrosis/pathology ; Receptors, Leukotriene B4/deficiency ; Receptors, Leukotriene B4/genetics ; Receptors, Leukotriene B4/immunology ; Th2 Cells/immunology ; Th2 Cells/pathology ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic |
| 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. |
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| Grant Information: | RR0109709 United States RR NCRR NIH HHS; R37 AI040618 United States AI NIAID NIH HHS; AI0508 United States AI NIAID NIH HHS; HL065228 United States HL NHLBI NIH HHS; P30 03,115,801 United States PHS HHS; R01 HL058723 United States HL NHLBI NIH HHS; R56 HL058723 United States HL NHLBI NIH HHS; HL058723 United States HL NHLBI NIH HHS; R01 HL065228 United States HL NHLBI NIH HHS |
| Substance Nomenclature: | 0 (CCL24 protein, human); 0 (Chemokine CCL24); 0 (Interleukin-5); 0 (Leukotrienes); 0 (Ltb4r1 protein, mouse); 0 (Receptors, Leukotriene B4); 1HGW4DR56D (Leukotriene B4); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase) |
| Entry Date(s): | Date Created: 20130718 Date Completed: 20140127 Latest Revision: 20211021 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC3931112 |
| DOI: | 10.1165/rcmb.2013-0009OC |
| PMID: | 23859654 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't