Peripheral mechanisms I: plasticity of peripheral pathways

Cough plays a vital role in protecting the lower airways from inhaled irritants, pollutants, and infectious agents. The cough reflex exhibits remarkable plasticity, such that in the context of infectious or inflammatory respiratory diseases such as asthma, chronic bronchitis, and idiopathic pulmonary fibrosis the cough reflex can become dysregulated, leading to a chronic cough. A chronic, nonproductive (dry) cough can rob sufferers of quality of life. Plasticity of the cough reflex likely involves multiple intersecting pathways within the airways, the peripheral nerves that supply them, and the central nervous system. While further studies are needed to determine the presence and relevance of many of these specific pathways in cough associated with chronic respiratory disease, the last decade has yielded unprecedented insight into the molecular identity of the ion channels and associated proteins that initiate and conduct action potentials in the primary sensory nerves involved in reflexes such as cough. We now know, for instance, that members of the transient receptor potential superfamily of nonselective cation channels function as transducers that convert specific external stimuli into neuronal activation. We also know that certain Na+ and K+ channels play specialized roles in regulating action potential discharge in irritant-sensing afferent nerves. In this chapter, we summarize the available information regarding factors that may modulate afferent neuron function acutely, via posttranslational modifications and over the longer term through neurotrophin-dependent alterations of the transcriptional programs of adult sensory neurons.