Transgenic smooth muscle expression of the human CysLT1 receptor induces enhanced responsiveness of murine airways to leukotriene D 4

Guochang Yang, Angela Franciska Haczku, Hang Chen, Viviane Martin, Helen Galczenski, Yaniv Tomer, Christopher R. Van Beisen, Jilly F. Evans, Reynold A. Panettieri, Colin D. Funk

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Cysteinyl leukotrienes (CysLTs) exert potent proinflammatory actions and contribute to many of the symptoms of asthma. Using a model of allergic sensitization and airway challenge with Aspergillus fumigatus (Af), we have found that Th2-type inflammation and airway hyperresponsiveness (AHR) to methacholine (MCh) were associated with increased LTD4 responsiveness in mice. To explore the importance of increased CysLT signaling in airway smooth muscle function, we generated transgenic mice that overexpress the human CysLT1 receptor (hCysLT1R) via the α-actin promoter. These receptors were expressed abundantly and induced intracellular calcium mobilization in airway smooth muscle cells from transgenic mice. Force generation in tracheal ring preparations ex vivo and airway reactivity in vivo in response to LTD4 were greatly amplified in hCysLT 1R-overexpressing mice, indicating that the enhanced signaling induces coordinated functional changes of the intact airway smooth muscle. The increase of AHR imposed by overexpression of the hCysLT1R was greater in transgenic BALB/c mice than in transgenic B6 × SJL mice. In addition, sensitization- and challenge-induced increases in airway responsiveness were significantly greater in transgenic mice than that of nontransgenic mice compared with their respective nonsensitized controls. The amplified AHR in sensitized transgenic mice was not due to an enhanced airway inflammation and was not associated with similar enhancement in MCh responsiveness. These results indicate that a selective hCysLT 1R-induced contractile mechanism synergizes with allergic AHR. We speculate that hCysLT1R signaling contributes to a hypercontractile state of the airway smooth muscle.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume286
Issue number5 30-5
DOIs
StatePublished - May 2004
Externally publishedYes

Keywords

  • Allergic airway inflammation
  • Asthma

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

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