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Plasticity of cholinergic and tachykinergic nerves: the convergence of the twain

Allison D. Fryer and David B. Jacoby

Division of Physiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205


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TWO NEURAL CONTROL MECHANISMS constrict the airways, cholinergic and noncholinergic. The cholinergic fibers arise in ganglia within the airway wall. These constrict the airways by releasing acetylcholine onto muscarinic receptors. Noncholinergic fibers arise in vagal ganglia at the base of the skull. These nerves constrict the airways by releasing tachykinins onto neurokinin receptors. The anatomically distinct origins of these two systems has allowed their isolation for study.

It has long been known that the functions of the two systems are changeable and that they respond to inflammatory stimuli that may be relevant to airway disease. As the function and/or expression of inhibitory M2 muscarinic receptors on cholinergic fibers is decreased, release of acetylcholine in the airways is increased after viral infections, inhalation of allergens, and exposure to ozone (10). This predictably increases bronchoconstriction and may also participate in the increased airway secretions characteristic of asthma and chronic obstructive pulmonary disease.

Likewise, the influence of tachykinergic nerves on bronchoconstriction may also be increased by inflammation. Tachykinin-mediated bronchoconstriction can be potentiated by both increased release and impaired degradation of these mediators. Such changes have been described in the same models that increase acetylcholine release.

Changes in the expression of tachykinins in sensory neurons have also been recognized, both in the airways and elsewhere. Neural plasticity is likely to be of central importance in the pathogenesis of chronic pain. Several forms of neural plasticity contribute to this process (14). One of these, the induced expression of tachykinins in sensory neurons of the Adelta type, which normally do not express tachykinins, is likely to be important in the response to inflammation.

In recent years, it has become evident that expression of tachykinins by sensory neurons supplying the lungs can also be changed. Allergen challenge (13) and viral infection of the lungs (2) both increase expression of tachykinins in vagal ganglia. Functional and histological analysis reveals that in these settings tachykinins are expressed not only by the usual C-fiber neurons (with cell bodies in the jugular ganglion) but also by neurons of the Adelta type, with cell bodies in the nodose ganglion. Thus inflammatory stimuli not only alter the function of existing tachykinergic neurons but also cause a phenotypic change in sensory neurons that did not previously express these neurotransmitters. Thus a process similar to that recognized in the somatosensory system is also present in the airway sensory fibers. This provides an attractive mechanism whereby bronchoconstriction, hypersecretion, neurogenic inflammation, and increased vascular permeability (all functions of tachykinins) might all be upregulated together.

Although a broad range of mediators may contribute to changes in tachykinin gene expression, work in several systems suggests that neurotrophins may be particularly important (3). This family of growth factors includes nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. By signaling through a family of receptor tyrosine kinases, neurotrophins have the capacity to mediate the sort of neural plasticity observed in the somatosensory system and airway sensory neurons. In addition to increasing tachykinin gene expression, neurotrophins increase expression of calcitonin gene-related peptide, the bradykinin B2 receptor, and the VR-1 vanilloid receptor, and may have important effects on ion channels, all of which may affect neural function. In the context of the airways, it may be significant that nerve growth factor levels are increased in asthma and in allergic rhinitis (1). Exogenous nerve growth factor causes airway hyperresponsiveness in guinea pigs (4), an effect that is blocked by blocking the neurokinin (NK)-1 receptor (the substance P receptor), strongly suggesting the involvement of tachykinins.

In the study by Wu and colleagues, one of the current articles in focus (Ref. 15, see p. L909 in this issue), the authors report the effects of interleukin-1beta on the responsiveness of ferret airways. Treatment with interleukin-1beta , either in vivo or in isolated airway segments in vitro, increased contractile responses to cholinergic stimulation. This could be blocked by depleting tachykinins or by the NK-1 receptor antagonist CP-99994. Careful immunohistological studies show expression of tachykinins by parasympathetic ganglia in the airway wall after treatment with interleukin-1beta . The conclusion is that increased synthesis and release of tachykinins by neurons intrinsic to the airways, which normally do not synthesize tachykinins, mediate increased airway responsiveness.

This new finding of inducible expression of tachykinins by ganglion cells within the airway wall is consistent with the findings of de Vries and colleagues (5), who showed that not only does exogenously applied nerve growth factor induce a tachykinin-mediated airway hyperresponsiveness but that it also does so in isolated tracheal tissues. As these tissues are physically separated from the vagal sensory neuron cell bodies, induction of tachykinin expression in the sensory nerves could not be responsible. However, the current finding that intrinsic airway neurons can be induced to express tachykinins may explain the ability of nerve growth factor to induce tachykinin-mediated hyperresponsiveness in the absence of vagal sensory ganglion cells.

How does interleukin-1beta induce this form of neural plasticity? An attractive possibility might be the observation that interleukin-1beta , acting synergistically with tumor necrosis factor-alpha , stimulates the expression of nerve growth factor (8) in lung fibroblasts (11) and epithelial cells (6). Thus interleukin-1beta , widely produced in inflammatory conditions of the airways, might be an important mediator of airway neural plasticity via its ability to induce nerve growth factor. Similar mechanisms appear to be important in the effects of interleukin-1beta on somatic sensory nerves. Injection of complete Freund's adjuvant into rat footpads causes hyperalgesia that is accompanied by increased interleukin-1beta , increased nerve growth factor, and increased substance P expression in the dorsal root ganglia. Injection of interleukin-1beta reproduced these findings, whereas the hyperalgesia was prevented by neutralizing nerve growth factor with antiserum (12).

There are other possible mechanisms for the effects of interleukin-1beta in this study. The effects of lipopolysaccharide on tracheal calcitonin gene-related peptide are mediated via the production of interleukin-1beta and depend on production of prostanoids (9), suggesting that effects of interleukin-1beta on cyclooxygenase-2 may be important. In visceral afferents in the cat, interleukin-1beta increases the activity of C fibers and sensitizes them to histamine (7). Thus in addition to effects on tachykinin expression, interleukin-1beta may have other effects on nerves that contribute to hyperresponsiveness.

The provocative studies of Wu and colleagues (15) in this issue suggest new mechanisms of airway hyperresponsiveness involving plasticity of the intrinsic parasympathetic neurons of the airways. Many important questions remain in understanding neural plasticity in the airways. What are the molecular mechanisms of the changes in gene expression? What other neurotransmitters are induced? What other stimuli can change airway neural gene expression? Are changes in gene expression in existing neurons or differentiation of neural stem cells responsible for the observed changes? What other forms might neural plasticity take in the airways (changes in receptors or structural changes in addition to changes in transmitter expression)? What is the role of neural plasticity in airway disease? and is it a potential therapeutic target? Understanding plasticity of the intrinsic neurons of the airways is one aspect of understanding airway neural plasticity in general, which in turn will contribute greatly to our understanding of the role of altered neural function in the pathogenesis of airway disease.


    FOOTNOTES

Address for reprint requests and other correspondence: A. D. Fryer, Div. of Physiology, Johns Hopkins Univ. Bloomberg School of Public Health, Baltimore, MD 21205 (E-mail: afryer{at}jhsph.edu).

10.1152/ajplung.00128.2002


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2.   Carr, MJ, Hunter DD, Jacoby DB, and Undem BJ. Expression of tachykinins in nonnociceptive vagal afferent neurons during respiratory viral infection in guinea pigs. Am J Respir Crit Care Med 165: 1071-1075, 2002[Abstract/Free Full Text].

3.   Carr, MJ, Hunter DD, and Undem BJ. Neurotrophins and asthma. Curr Opin Pulm Med 7: 1-7, 2001[Medline].

4.   De Vries, A, Dessing MC, Engels F, Henricks PA, and Nijkamp FP. Nerve growth factor induces a neurokinin-1 receptor-mediated airway hyperresponsiveness in guinea pigs. Am J Respir Crit Care Med 159: 1541-1544, 1999[Abstract/Free Full Text].

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15.   Wu, ZX, Satterfield BE, Fedan JS, and Dey RD. Interleukin-1beta -induced airway hyperresponsiveness involves enhanced substance P expression in intrinsic neurons of ferret airway. Am J Physiol Lung Cell Mol Physiol 283: L909-L917, 2002.


Am J Physiol Lung Cell Mol Physiol 283(5):L907-L908
1040-0605/02 $5.00 Copyright © 2002 the American Physiological Society