Characterization of bronchopulmonary vagal afferent C-fiber subtypes

The majority of nerves innervating the lungs are vagal bronchopulmonary C-fibers. They are stimulated by inflammation such as in asthma and COPD or pulmonary congestion and cause changes in breathing pattern, reflex coughing, bronchoconstriction, vascular leakage and mucus hypersecretion. The critical characterization of these nerves is a prerequisite for our understanding of their role in pulmonary physiology and pathophysiology. Bronchopulmonary C-fibers have been classified into two subgroups, pulmonary and bronchial C-fibers, based on vascular accessibility. Some chemicals stimulate one type more than the other. The difference may be related to the difference in the properties of the fibers themselves or to the difference in biochemical or physical properties of the environment in which these fiber endings are embedded.;Bronchopulmonary C-fiber cell bodies are located in either the nodose or jugular ganglion and the cell bodies of these two ganglia originate from different embryological origins: nodose cell bodies originate from the epibranchial placode, whereas the jugular cell bodies originate from the neural crest. This different embryological origin may cause a difference in phenotype and function. The central hypothesis of this thesis is that there are two distinct subtypes of vagal bronchopulmonary C-fibers based on the ganglionic (and thus embryological) origins of their cell bodies.;The nodose and jugular C-fibers were characterized based on their anatomical location, their neuropeptide content, as well as their chemical activation profile. We found that both nodose and jugular C-fibers innervate the lungs (whereas only jugular C-fibers innervate trachea and main bronchi). In addition, both nodose and jugular C-fibers innervating the lungs are different in neuropeptide content. Only half of nodose C-fiber neurons contain substance P, whereas almost all of the jugular C-fiber neurons express substance P. Jugular and nodose bronchopulmonary C-fibers can also be differentiated based on their chemical activation profile. By combining the extracellular recordings and patch clamp studies on cell bodies of identified lung C-fibers, we found that both 5-Hydroxytryptamine (5-HT) and adenosine directly stimulated nodose (placodal) C-fibers but not jugular (neural crest) C-fibers in guinea pig lung. These effects were due to the stimulation of ionotropic 5-HT3 receptors, and G protein-coupled adenosine A1 and A2A receptor subtypes, respectively.;A better understanding of the differences in vagal bronchopulmonary C-fiber subtypes in terms of their distribution, neuropeptide content and pharmacological properties is required for an accurate assessment of the physiological role of C-fibers, as well as their role in the pathophysiology of respiratory diseases. The chemical activation profile suggests that the participation of one type of C-fiber may predominate over the other in different airway pathologies. For example, inflammation localized in the large airways may favor activation of the neuropeptide-laden jugular C-fibers, whereas lung parenchymal inflammation or other conditions such as hypoxia or pulmonary congestion may favor nodose C-fiber type activation via chemical mediators like adenosine. A more refined understanding of the reflex pathways evoked by nodose versus jugular C-fiber stimulation, and the development of drugs aimed at selectively inhibiting the two types of C-fibers will be required before the role of each type of vagal bronchopulmonary C-fiber in physiology and pathophysiology is completely understood.