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Transgenic smooth muscle expression of the human CysLT₁ receptor induces enhanced responsiveness of murine airways to leukotriene D₄

¹Center for Experimental Therapeutics, Department of Pharmacology, ²Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104; and ³Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486

Submitted 27 October 2003 ; accepted in final form 15 December 2003

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 -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 hCysLT₁R-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 x 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 hCysLT₁R-induced contractile mechanism synergizes with allergic AHR. We speculate that hCysLT₁R signaling contributes to a hypercontractile state of the airway smooth muscle.

asthma; allergic airway inflammation

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