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: Sergei I Ochkur, Cheryl A Protheroe, Wen Li, Dana C Colbert, Katie R Zellner, Hua-Hao Shen, Andrew D Luster, Charles G Irvin, James J Lee, Nancy A Lee
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 49 Issue 6 Pg. 1074-84 (Dec 2013) ISSN: 1535-4989 [Electronic] United States
• PMID: 23859654 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CCL24 protein, human
• Chemokine CCL24
• Interleukin-5
• Leukotrienes
• Ltb4r1 protein, mouse
• Receptors, Leukotriene B4
• Leukotriene B4
• Arachidonate 5-Lipoxygenase

Topics

• Animals
• Arachidonate 5-Lipoxygenase (deficiency, genetics, immunology)
• Bronchial Hyperreactivity (immunology)
• Chemokine CCL24 (genetics, immunology)
• Disease Models, Animal
• Eosinophils (immunology, pathology)
• Humans
• Interleukin-5 (immunology)
• Leukotriene B4 (immunology)
• Leukotrienes (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Pneumonia (etiology, immunology, pathology)
• Pulmonary Fibrosis (etiology, immunology, pathology)
• Receptors, Leukotriene B4 (deficiency, genetics, immunology)
• Th2 Cells (immunology, pathology)