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Cooperation between Mast Cells and Neurons Is Essential for Antigen-Mediated Bronchoconstriction¹

Jaime M. Cyphert^*, Martina Kovarova, Irving C. Allen^*, John M. Hartney^*, Dennis L. Murphy, Jürgen Wess and Beverly H. Koller^2,*,

^* Curriculum in Genetics and Molecular Biology and Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892; and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892

Mast cells are important sentinels guarding the interface between the environment and the body: a breach in the integrity of this interface can lead to the release of a plethora of mediators that engage the foreign agent, recruit leukocytes, and initiate adaptive physiological changes in the organism. While these capabilities make mast cells critical players in immune defense, it also makes them important contributors to the pathogenesis of diseases such as asthma. Mast cell mediators induce dramatic changes in smooth muscle physiology, and the expression of receptors for these factors by smooth muscle suggests that they act directly to initiate constriction. Contrary to this view, we show herein that mast cell-mediated bronchoconstriction is observed only in animals with intact innervation of the lung and that serotonin release alone is required for this action. While ablation of sensory neurons does not limit bronchoconstriction, constriction after Ag challenge is absent in mice in which the cholinergic pathways are compromised. Linking mast cell function to the cholinergic system likely provides an important means of modulating the function of these resident immune cells to physiology of the lung, but may also provide a safeguard against life-threatening anaphylaxis during mast cell degranulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants NIH/NHLBI R01 HL080697 and HL068141 (to B.H.K.).

² Address correspondence and reprint requests to Dr. Beverly H. Koller, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, 5067 Genetic Medicine Building, CB 7264, 120 Mason Farm Road, Chapel Hill, NC 27599. E-mail address: treawouns{at}aol.com

³ Abbreviations used in this paper: ASM, airway smooth muscle; ACh, acetylcholine; BALF, bronchoalveolar lavage fluid; B6, C57BL/6; 5LO, 5-lipoxygenase; FOT, forced oscillatory technique; G, tissue damping; H, tissue elastance; LT, leukotriene; MCh, methacholine; mAChR, muscarinic acetylcholine receptor; nAChR, nicotinic acetylcholine receptor; PAR2, protease-activated receptor 2; PCPA, 4-chloro-DL-phenylalanine; R_aw, airway resistance; R_L, lung resistance; Wsh/Wsh, C57BL/6 Kit^W-sh/Kit^W-sh.

⁴ The online version of this article contains supplemental material.