Tachykinins airway responses

Although tachykinins are important in the airway response to certain interventions, there appears to be little or no tachykinin tone in the absence of intervention. In non-asthmatic or stable asthmatic human airways, neither the NEP inhibitor thiorphan (Cheung et /., 1992, 1993) nor the combined Nkl/Nk2 receptor antagonist FK224 (Ichinose et al., 1992) has any effect on baseline specific airways resistance. Likewise, alterations in NEP activity do not contribute to the enhanced bronchoconstrictive responses to NkA observed in patients with mild asthma. Asthmatic patients respond to inhaled thiorphan with an increase in NkA-induced bronchoconstriction similar in magnitude to that documented in non-asthmatic subjects (Cheung et al., 1992, 1993). 

The potential for amplification of airway responses is intriguing. Mast cell products released by specific antigen-IgE interactions could stimulate C-fibers to release tachykinins, and these tachykinins could then stimulate the mast cells that fell within the dendritic network of the particular nerve involved. Therefore, local antigen-induced stimulation of mast cells could spread far beyond the diffusion distance for the antigen in question. The specific relevance of this proposed amplification mechanism to human disease has not been evaluated. 

THOMPSON, J.E., SCYPINSKI, L GORDON, T. SHEPPARD, D. (1987) Tachykinins mediate the acute increase in airway responsiveness caused by toluene diisocyanate in guinea pigs. American Review of Respiratory Disease, 136, 43-49. 

Kwong K, Wu ZX, Kashon ML, Krajnak KM, Wise PM, Lee LY (2001) Chronic smoking enhances tachykinin synthesis and airway responsiveness in Guinea pigs. Am J Respir Cell Mol Biol 25 299-305... 

The stimulation of C fibers by capsaicin causes a subset of sensory airway neurons to release several neuropeptides, which include tachykinin, substance P and neurokinin A. In addition to capsaicin, other endogenous mediators including histamine, prostaglandins and bradykinins can also result in their release. These neuropeptides are responsible for neurogenic inflammation, which is characterized by vasodilation, mucus secretion, plasma protein extravasation, increased expression of the adhesion molecules and bronchoconstriction. 

Ellis, J.L., Undem, B.J., Kays, J.S. etal. (1993). Pharmacological examination of receptors mediating contractile responses to tachykinins in airways isolated from human, guinea-pig and hamster. J. Pharmacol. Exp. Ther. 267, 95-101. 

These observations on sensory nerve endings can probably be extended mechanistically and transposed to other sites (e.g. the airways). In skin it seems certain that a local axon reflex is involved in the triple response described by Lewis, whereby there is flush, flare and wheal manifestation of which denotes neurogenic inflammation. Many of these manifestations can be blocked with bradykinin and tachykinin receptor antagonists, and antihistamines, used in concert. It is now presumed that these basic observations in the skin can be applied to conjunctivae and the airways, and there is every reason to suppose that much the same events are involved in (defensive) reaction to exogenous irritant chemicals. 

Early work on the effects of JP-8 inhalation in rats showed an inverse relationship between increases in airway epithelial permeability ("TcDTPA clearance) and decreased concentrations of the tachykinin substance P in bronchoalveolar lavage fluid (BALF) (Hays et al. 1995). Substance P has a strong affinity for the neurokinin receptor NK, one of a family of plasma-membrane-bound neurokinin receptors that mediate protective reflex responses—such as bronchoconstriction, increased vascular permeability, vasodilatation, mucus secretion, and enhanced mucociliary activity—to airway exposure to mechanical or chemical irritants. 

Interleukin-17 is predominantly secreted by activated CD4 lymphocytes. IL-17 can elicit granulopoiesis in vitro (71) and in vivo (72) and can induce an array of proinflammatory cytokines in human macrophages, including TNF, IL-1 p, IL-6, and IL-12 (73). Moreover, two reports show that IL-17 can result in neutrophilic recruitment in the lung by augmenting chemokine expression (74) and by the release of tachykinins (75). It has also been observed that IL-17 can also activate neutrophils in association with their recruitment into the airway in vivo (76). Recently, we have shown IL-17 receptor signaling is required for normal chemokine secretion in the lung in response to K. pneumoniae infection (77). As IL-17 is principally elaborated by CD4+ T cells, this may represent one mechanism by which HIV-infected individuals with diminished CD4 T cells are predisposed to bacterial pneumonia. 

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