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Published ahead of print on April 22, 2005, doi:10.1164/rccm.200502-205OC
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American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 161-167, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200502-205OC

Original Article

Requirement for Leukotriene B4 Receptor 1 in Allergen-induced Airway Hyperresponsiveness

Nobuaki Miyahara, Katsuyuki Takeda, Satoko Miyahara, Shigeki Matsubara, Toshiyuki Koya, Anthony Joetham, Elangovan Krishnan, Azzeddine Dakhama, Bodduluri Haribabu and Erwin W. Gelfand

Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky

Correspondence and requests for reprints should be addressed to Erwin W. Gelfand, M.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: gelfande{at}njc.org

Rationale: Leukotriene B4 (LTB4) is a rapidly synthesized, early leukocyte chemoattractant that signals via its cell surface receptor, leukotriene B4 receptor 1 (BLT1), to attract and activate leukocytes during inflammation. A role for the LTB4–BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation is not well defined. Objectives: To define the role of the LTB4 receptor (BLT1) in the development of airway inflammation and altered airway function. Methods: BLT1-deficient (BLT1–/–) mice and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged with ovalbumin via the airways. Airway responsiveness to inhaled methacholine, bronchoalveolar lavage fluid cell composition and cytokine levels, and lung inflammation and goblet cell hyperplasia were assessed. Results: Compared with wild-type mice, BLT1–/– mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased interleukin (IL)-13 production both in vivo, in the bronchoalveolar lavage fluid, and in vitro, after antigen stimulation of lung cells in culture. Intracellular cytokine staining of lung cells revealed that bronchoalveolar lavage IL-13 levels and numbers of IL-13+/CD4+ and IL-13+/CD8+ T cells were also reduced in BLT1–/– mice. Reconstitution of sensitized and challenged BLT1–/– mice with allergen-sensitized BLT1+/+ T cells fully restored the development of airway hyperresponsiveness. In contrast, transfer of naive T cells failed to do so. Conclusion: These data suggest that BLT1 expression on primed T cells is required for the full development of airway hyperresponsiveness, which appears to be associated with IL-13 production in these cells.

Key Words: airway responsiveness • cytokines • lipid mediators • lung inflammation • T cells




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