“Tasting” the airway lining fluid

Homeostatic regulation of the balanced chemical composition of the mucosal lining fluid requires appropriate monitoring. Very recently, we have identified a novel epithelium-mediated mechanism for detection of potentially harmful substances that operates in addition to pattern recognition receptors and TLRs. Specialized airway epithelial cells, called brush cells, were identified to be cholinergic. They utilize molecular components of the canonical bitter (dangerous substances, bacterial products) taste transduction cascade as known from the tongue taste buds such as the G-protein -gustducin, phospholipase C beta 2 (PLC2), transient receptor potential cation channel subfamily M member 5 (TRPM5), and the G-protein coupled taste receptors Tas1R and Tas2R families. In the mouse trachea, both mTas2R105 and mTas2R108, for cycloheximide and denatonium, respectively, were detected in the cholinergic cell population. Denatonium, cycloheximide and 3-oxo-C12-homoserine-lacton, a Pseudomonas aeruginosa quorum-sensing molecule, lead to increase in intracellular calcium concentration with subsequent release of acetylcholine and initiation of generalized avoidance reflexes through the excitation of cholinoreceptive sensory nerve fibers in the vicinity of chemosensory cells. Application of bitter substances to the tracheal mucosa of spontaneously breathing mice decreases respiration rate (RR) in an epithelium-dependent manner which is sensitive to mecamylamine, a general nicotinic antagonist. In addition, denatonium also directly activates vagal sensory nerve fibers resulting in short pauses in breathing (“respiratory events”) that are augmented by mecamylamine. Moreover, denatonium has also direct local effects such as decreasing particle transport speed at the mucosal surface.