Abstract
Protease-activated receptor 2 (PAR2), a G protein-coupled receptor expressed in airway epithelia and smooth muscle, plays an important role in airway inflammation. In this study, we demonstrated that activation of PAR2 induces mucus secretion from the human airway gland and examined the underlying mechanism using the porcine and murine airway glands. The mucosa with underlying submucosal glands were dissected from the cartilage of tissues, pinned with the mucosal side up at the gas/bath solution interface of a physiological chamber, and covered with oil so that secretions from individual glands could be visualized as spherical bubbles in the oil. Secretion rates were determined by optical monitoring of the bubble diameter. The Ca2+-sensitive dye Fura2-AM was used to determine intracellular Ca2+ concentration ([Ca2+]i) by means of spectrofluorometry. Stimulation of human tracheal mucosa with PAR2-activating peptide (PAR2-AP) elevated intracellular Ca2+ and induced glandular secretion equal to approximately 30% of the carbachol response in the human airway. Porcine gland tissue was more sensitive to PAR2-AP, and this response was dependent on Ca2+ and anion secretion. When the mouse trachea were exposed to PAR2-AP, large amounts of secretion were observed in both wild type and ΔF508 cystic fibrosis transmembrane conductance regulator mutant mice but there is no secretion from PAR-2 knock out mice. In conclusion, PAR2-AP is an agonist for mucus secretion from the airway gland that is Ca2+-dependent and cystic fibrosis transmembrane conductance regulator-independent.
Highlights
Airway submucosal glands produce most of the airway mucus, which is essential for mucociliary clearance
The secretion rate varied among the glands but all the carbachol-responding glands were activated by Protease-activated receptor 2 (PAR2)-AP
PAR2-activating peptide (PAR2-AP) was a weak enhancer of mucin secretion in primary human airway epithelial cells [19], which was believed to indicate that PAR2 is not a significant contributor to mucus regulation
Summary
Airway submucosal glands produce most of the airway mucus, which is essential for mucociliary clearance. The submucosal gland secretes various antimicrobial components, such as lysozyme, to protect the airway from bacteria [1]. Adequate mucus secretion from airway submucosal glands is essential to maintain the airway defense system. Overproduction of mucus secretion from airway glands may lead to airway diseases, such as chronic obstructive lung disease and asthma [3]. Secretion from airway glands is mainly controlled by central parasympathetic input [4]. In addition to the autonomic nervous system, airways have abundant intrinsic neurons and pathogen-sensing receptors, and their activation induces mucus secretion from airway glands via a neuronal mediator such as substance P or vasoactive intestinal peptide (VIP) [2,5]. There is accumulating evidence supporting an important role for these local reflexes in the airway innate immune response
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