Mast cell mediator-induced modulation of the electrical excitability of autonomic and sensory nerves in the airways.

摘要

Many of the symptoms of allergic airway disease such as sneezing, coughing, excessive secretions, reflex bronchoconstriction, and dyspnea occur secondary to changes in the activity of the airway nervous system, and may be explained largely as a consequence of allergen-induced neuromodulation. Mediators associated with allergic inflammation, particularly those derived from activated mast cells, can modulate primary afferent nerves and their connecting neurons in the central nervous system (CNS), as well as autonomic efferent neurons innervating the airways. This modulation can take the form of acute electrophysiological changes, or more persistent phenotypic changes at the level of gene transcription.;The vagus nerves provide much of the innervation to the lower respiratory tract carrying both sensory afferent nerves, and parasympathetic efferent nerves between the lower respiratory tract and the CNS. This thesis addresses the acute consequences of allergen-induced mast cell activation on the electrical activity of nerves within the lower respiratory tract, namely of vagal sensory C-fibers on the afferent side, and parasympathetic cholinergic ganglionic neurons on the efferent side. First described are the anatomical and electrophysiological properties of parasympathetic ganglionic neurons in mouse airways, following which, we demonstrate that allergen-induced contraction of trachea isolated from sensitized mice is dependent on the activation of these parasympathetic ganglionic neurons by mast cell-derived 5-HT. In a separate set of studies we report that nodose-type C-fibers innervating guinea pig lungs are activated by ATP released from the tissues during histamine-induced bronchoconstriction, and that in the lungs of sensitized animals, allergen activates these C-fibers in a manner that is dependent on histamine and ATP.;The results presented in this thesis provide evidence for direct interaction between mast cells and vagal nerves within the airways, and show that such interactions can lead to activation of both sensory afferent and parasympathetic efferent nerves. Moreover, we describe the mechanisms underlying the mast cell-mediated activation of these nerves. Activation leads to increases in the number and frequency of action potentials arising in the CNS from nerve terminals in the respiratory tract; increases that may explain many of the acute symptoms of the allergic response.