Sensory mechanisms in the human upper airway - Role of TRP ion channels

Detta är en avhandling från Clinical Chemistry and Pharmacology, Dept of Laboratory Medicine

Sammanfattning: The nasal mucosa is richly innervated with sensory nerves having the ability to detect changes in the environment and mediate symptoms such as secretion and itch. Some TRP ion channels such as TRPV1 and TRPA1 are abundantly expressed in sensory nerves and respond to a wide variety of stimuli, including irritants, inflammatory mediators and temperatures. Another interesting TRP ion channel is TRPV4, which is present in the airway epithelium and capable of sensing warm temperatures and osmotic changes. TRP ion channels may have important roles in airway physiology and pathology. We studied the responses to TRP activation in the upper airway of healthy subjects and patients with allergic rhinitis. Furthermore, we examined the effect of TRPV1 antagonism in allergic rhinitis. We showed that activation of TRPV1 and TRPA1 lead to secretion of MUC5B from submucosal glands, and that TRPV1 activation results in an enhanced rhinorrhea and itch response in patients with allergic rhinitis during pollen season. However, our initial studies were unable to demonstrate any symptomatic relief by a TRPV1 antagonist in allergic rhinitis. Analyses of mRNA of different TRP ion channels indicated TRPV1 expression in nasal epithelium, but we were unable to detect any functional response in ciliated epithelial cells. TRPV4 presented the highest mRNA expression of tested TRP ion channels, and further functional studies implied that TRPV4 may be involved in ciliary beat frequency regulation in primary human epithelial cells. Our studies indicate that TRPV1 expressing sensory neurons and possibly TRPV1 itself are involved in sensory hyperresponsiveness during allergic inflammation, and have a role in itch and mucus secretion. In addition, we suggest that TRPV1 and TRPV4 may contribute to mucociliary defence due to the proposed role of TRPV4 in epithelial ciliary regulation and of TRPV1 in secretion. Further studies are warranted to clarify the roles of TRPV1, TRPA1 and TRPV4 in human airway physiology and in airway disease.