Induction of tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation.

Abstract

Substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) have potent proinflammatory effects in the airways. They are released from sensory nerve endings originating in jugular and dorsal root ganglia. However, the major sensory supply to the airways originates from the nodose ganglion. In this study, we evaluated changes in neuropeptide biosynthesis in the sensory airway innervation of ovalbumin-sensitized and -challenged guinea pigs at the mRNA and peptide level. In the airways, a threeto fourfold increase of SP, NKA, and CGRP, was seen 24 h following allergen challenge. Whereas no evidence of local tachykinin biosynthesis was found 12 h after challenge, increased levels of preprotachykinin (PPT)-A mRNA (encoding SP and NKA) were found in nodose ganglia. Quantitative in situ hybridization indicated that this increase could be accounted for by de novo induction of PPT-A mRNA in nodose ganglion neurons. Quantitative immunohistochemistry showed that 24 h after challenge, the number of tachykinin-immunoreactive nodose ganglion neurons had increased by 25%. Their projection to the airways was shown. Changes in other sensory ganglia innervating the airways were not evident. These findings suggest that an induction of sensory neuropeptides in nodose ganglion neurons is crucially involved in the increase of airway hyperreactivity in the late response to allergen challenge. ( J. Clin. Invest. 1996. 98:2284-2291.)

Immediate sensory nerve-mediated respiratory responses to irritants in healthy and allergic airway-diseased mice

“…Sensory nervedependent obstruction in rodents may be mediated by axonal neuropeptide release (4,5,22,37). Recent data suggest an increased expression of neuropeptides in airway sensory nerves in allergic inflammation, perhaps due to enhanced NGF release (17,19,33). This may reflect elevated expression in A␦-fibers (19).…”

Inflammation-Induced Plasticity of the Afferent Innervation of the Airways

“…Similarly, within 24 hr of allergen inhalation, there is a 3-to 5-fold elevation in the amount of substance P, NK-A and CGRP immunoreactivity in the lungs of guinea pigs (17). Although decreased enzymatic breakdown of tachykinins within the airways may contribute to this elevation (57), at least a component of the increased content of tachykinins stems from an increase in tachykinin synthesis (17). A somewhat surprising observation was that, following allergen challenge, nodose neurons whose axons projected to the airways were shown to express tachykinins.…”

“…This was surprising, as nodose fibers that innervate guinea pig airways do not normally contain immunoreactive tachykinins. In sensitized guinea pigs not challenged with antigen, only 1% of cell bodies of airways innervating nodose fibers were immunoreactive for substance P. In challenged guinea pigs, approximately 10% of cell bodies of nodose neurons retrogradely labeled from the airways were immunoreactive for substance P (17). Physiologic studies support the hypothesis that allergic inflammation causes a substantive qualitative change in the type of airway afferent fibers that contained tachykinins, such that non-nociceptive (capsaicin-insensitive, low-threshold mechanosensors) as well as nociceptive airway afferent fibers contribute to the neuropeptide innervation (Figure 1) (58).…”

“…In sensitized guinea pigs, challenge of the nasal mucosa with the sensitizing allergen enhanced the synthesis of substance P and CGRP in the cell bodies of trigeminal ganglion neurons and the axonal transportation of these peptides to their terminals in the nasal mucosa (56). Similarly, within 24 hr of allergen inhalation, there is a 3-to 5-fold elevation in the amount of substance P, NK-A and CGRP immunoreactivity in the lungs of guinea pigs (17). Although decreased enzymatic breakdown of tachykinins within the airways may contribute to this elevation (57), at least a component of the increased content of tachykinins stems from an increase in tachykinin synthesis (17).…”

“…Under normal conditions the tachykinergic innervation to the airways is thought to be derived exclusively from neurons that project nociceptive-like C fibers. In the guinea pig and rat airways, the cell bodies of the vagal afferent fibers that contain tachykinins are C fibers whose cell bodies reside in the jugular ganglia (12,14,16,17).…”