Chapter 11. The Role of Tachykinins in Pulmonary Disease

Abstract

This chapter discusses the possible role of neuropeptide substance P (SP) and related peptides in airway inflammatory conditions commonly known as asthma, bronchitis, and rhinitis. The biological effects of SP on nonneuronal tissues, which result directly from SP release following C-fiber activation, include stimulation of smooth muscle contraction, exocrine and endocrine gland secretion, and endothelial cell stimulation, leading to vasodilation, plasma extravasation, and neutrophil infiltration. The mammalian tachykinin peptides include SP, neurokinin A and B (NKA, NKB), and the N-terminally extended forms of NKA that include neuropeptide K (NPK) and neuropeptide (NPγ). Agonist activity is defined by the shared carboxy terminal domain (Phe-X-Gly-Leu-Met-NH 2 ), whereas the amino terminal domains determine receptor binding selectivity. These mammalian tachykinin polypeptides are derived from two distinct genes, the SP/NKA gene, and the NKB gene. Several tachykinin genes, with their multiple RNA splicing and post-translational processing mechanisms, generate substantial diversity in the tachykinin peptides that can be produced. The three mammalian tachykinin receptors have been cloned and shown to be the members of the G-protein coupled receptor family. They are coupled to inositol phospholipid metabolism and a rise in the cytosolic free calcium concentration. Each of the three receptors, which are termed neurokinin-1 (NK 1 ), NK 2 , and NK 3 , displays a moderate degree of selectivity for SP, NKA (also NPK and NPγ), and NKB, respectively. The vagal nerves contain afferent SP-immunoreactive nerve fibers from the lung. The cell bodies of these afferent C-fibers in the dorsal root ganglia (nodose ganglion) produce SP, 90% of which is transported into the peripheral vagal branches. Capsaicin-sensitive C-fibers are also known as polymodal nociceptive afferents, which means they are activated by thermal, mechanical, and chemical stimuli at their nerve endings. This is a key observation regarding the possible role of tachykinin-induced neurogenic inflammation in asthma and bronchitis. In addition to SP, C-fibers also contain NKA, NPK, and possibly NPγ, all very potent agonists at NK 2 receptors that can be coreleased in the lung upon afferent stimulation.