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Published ahead of print on April 22, 2005, doi:10.1164/rccm.200502-205OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 2, July 2005, 161-167

A more recent version of this article appeared on July 15, 2005
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Submitted on February 9, 2005
Accepted on April 15, 2005

Requirement for the Leukotriene B4 Receptor-1 in Allergen-Induced Airway Hyperresponsiveness

Nobuaki Miyahara1, Katsuyuki Takeda1, Satoko Miyahara1, Shigeki Matsubara1, Toshiyuki Koya1, Anthony Joetham1, Elangovan Krishnan2, Azzeddine Dakhama1, Bodduluri Haribabu2, and Erwin W Gelfand1*

1 Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO, USA, 2 Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY, USA

* To whom correspondence should be addressed. E-mail: gelfande{at}njc.org.

Rationale: Leukotriene B4 (LTB4) is a rapidly synthesized, early leukocyte chemoattractant that signals via its cell surface receptor, 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 to wild-type mice, BLT1-/- mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased IL-13 production both in vivo, in the BAL fluid, and in vitro, following antigen stimulation of lung cells in culture. Intracellular cytokine staining of lung cells revealed that BAL 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: T cells, cytokines, lipid mediators, lung inflammation, airway responsiveness




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