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, Erwin W. Gelfand

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)161-167
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume172
Issue number2
DOIs
Publication statusPublished - Jul 15 2005
Externally publishedYes

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Leukotriene B4 Receptors
Interleukin-13
Allergens
T-Lymphocytes
Goblet Cells
Leukotriene B4
Methacholine Chloride
Ovalbumin
Bronchoalveolar Lavage Fluid
Inflammation
Hyperplasia
Leukocytes
Cytokines
Lung
Chemotactic Factors
Cell Surface Receptors
Bronchoalveolar Lavage
Intraperitoneal Injections
Pneumonia
Cell Culture Techniques

Keywords

  • Airway responsiveness
  • Cytokines
  • Lipid mediators
  • Lung inflammation
  • T cells

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Requirement for leukotriene B4 receptor 1 in allergen-induced airway hyperresponsiveness. / Miyahara, Nobuaki; Takeda, Katsuyuki; Miyahara, Satoko; Matsubara, Shigeki; Koya, Toshiyuki; Joetham, Anthony; Krishnan, Elangovan; Dakhama, Azzeddine; Haribabu, Bodduluri; Gelfand, Erwin W.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 172, No. 2, 15.07.2005, p. 161-167.

Research output: Contribution to journalArticle

Miyahara, N, Takeda, K, Miyahara, S, Matsubara, S, Koya, T, Joetham, A, Krishnan, E, Dakhama, A, Haribabu, B & Gelfand, EW 2005, 'Requirement for leukotriene B4 receptor 1 in allergen-induced airway hyperresponsiveness', American Journal of Respiratory and Critical Care Medicine, vol. 172, no. 2, pp. 161-167. https://doi.org/10.1164/rccm.200502-205OC
Miyahara, Nobuaki ; Takeda, Katsuyuki ; Miyahara, Satoko ; Matsubara, Shigeki ; Koya, Toshiyuki ; Joetham, Anthony ; Krishnan, Elangovan ; Dakhama, Azzeddine ; Haribabu, Bodduluri ; Gelfand, Erwin W. / Requirement for leukotriene B4 receptor 1 in allergen-induced airway hyperresponsiveness. In: American Journal of Respiratory and Critical Care Medicine. 2005 ; Vol. 172, No. 2. pp. 161-167.
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AU - Koya, Toshiyuki

AU - Joetham, Anthony

AU - Krishnan, Elangovan

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AU - Haribabu, Bodduluri

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N2 - 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.

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KW - T cells

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