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* Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908;
Division of Allergy and Clinical Immunology, Department of Internal Medicine, Johns Hopkins University, Baltimore, MD 21224;
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520;
Department of Pathology, Yale University School of Medicine, New Haven, CT 06519; and
¶ Pathology and Laboratory Medicine Service, Veterans Affairs Connecticut Health Care System, West Haven, CT 06516
Exaggerated levels of IL-13 and leukotriene (LT) pathway activation frequently coexist at sites of Th2 inflammation and in tissue fibrotic responses. However, the relationship(s) between the IL-13 and LTs in these responses have not been defined. We hypothesized that the 5-lipoxygenase (5-LO) pathway of LT metabolism plays an important role in the pathogenesis of IL-13-induced chronic inflammation and remodeling. To test this hypothesis, we evaluated the effects of IL-13 on components of the 5-LO metabolic and activation pathways. We also compared the effects of transgenic IL-13 in C57BL/6 mice with wild-type and null 5-LO genetic loci. These studies demonstrate that IL-13 increases the levels of mRNA encoding cytosolic phospholipase A2, LTA4 hydrolase, and 5-LO-activating protein without altering the expression of 5-LO, LTC4 synthase, LTB4 receptors 1 and 2, and cysteinyl-LT receptors 1 and 2. They also demonstrate that this activation is associated with the enhanced accumulation of LTB4 but not of cysteinyl-LTs. Furthermore, they demonstrate that this stimulation plays a critical role in the pathogenesis of IL-13-induced inflammation, tissue fibrosis, and respiratory failure-induced death while inhibiting alveolar remodeling. Lastly, mechanistic insights are provided by demonstrating that IL-13-induced 5-LO activation is required for optimal stimulation and activation of TGF-
1 and the inhibition of matrix metalloproteinase-12. When viewed in combination, these studies demonstrate that 5-LO plays an important role in IL-13-induced inflammation and remodeling.
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