Airway obstructive diseases are significant illnesses with a high prevalence in current society. The exact mechanism by which airways become hyperresponsive to stimuli is unknown, although several potential system dysfunctions have been proposed. One etiology hypothesized to be responsible for this hyperresponsiveness is an abnormality in the neural control of airway smooth muscle. We intend to investigate this by measuring the membrane electrical characteristics of parasympathetic airway microganglia in normal rabbits and in a horse radish peroxidase sensitized, IgE producing rabbit model of bronchial hyperresponsiveness. We hypothesize that neuromodulation of the efferent motor pathway responsible for airway smooth muscle tone occurs at the ganglionic level, that this ganglia are not simple neurotransmission relay stations, and that this modulation is altered in bronchially hyperresponsive rabbits. Additionally, the neuromuscular junction is another potential site for modulation. We believe that investigation into this area will broaden knowledge of the pathophysiology of human airway obstructive diseases and hope that significant advancements in the treatment of these diseases will be achieved. The potential neuromodulators which may be dysfunctional in airway obstructive diseases include substances acting at muscarinic, adrenergic, peptidergic, and autacoid receptors. These will be examined using in vitro intracellular electrophysiological recordings from the pulmonary ganglionic neurons and the smooth muscle, applying specific agonists acting at the receptor groups listed above, and also by using specific antagonists to inhibit nerve stimulation evoked electrical events which are neuromodulatory in nature, such as slow depolarizations. In addition, it is possible that afferent sensory structures communicate and modulate the efferent motor pathway via en passant or axon-axon reflexes. We will investigate this potential mechanism of innervation by performing chronic denervation surgeries and by the use of capsaicin, looking for differences between animals with afferent denervation to those in control animals. In order to discover the cellular mechanism of modulatory changes, we will perform primary culture of the airway microganglia and analyze currents with the patch voltage-clamp technique. With this combination of techniques - intracellular recording, primary culture, and patch voltage-clamp recording - our aim will be to illuminate at the cellular level the pathophysiological basis of bronchial hyperresponsiveness and thus broaden the therapeutic methods available to treat both asthma and other airway obstructive diseases.
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