American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 138-141, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.F260
Airway Neural Plasticity
The Nerves They Are A-Changin'
David B. Jacoby
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Address correspondence to: David B. Jacoby, M.D., Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: djacoby{at}jhmi.edu
Abbreviations: nerve growth factor, NGF • neurotrophin receptor, NTR • vanilloid receptor-1, VR1
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Introduction
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Bronchoconstriction is mediated by two anatomically and functionally distinct neural systems. Cholinergic fibers arise in parasympathetic ganglia in the airway walls, and cause bronchoconstriction by releasing acetylcholine onto smooth muscle M3 muscarinic receptors. Noncholinergic fibers arise in sensory ganglia in the vagus, and contribute to bronchoconstriction both by providing the afferent limb of a reflex arc and by releasing tachykinins onto neurokinin receptors on the smooth muscle. These systems allow the airway to respond both to exogenous irritants and to endogenous mediators. However, changes in the structure and function of the nerves themselves in response to changing conditions, a phenomenon known as neural plasticity, may also contribute to the pathophysiology of airway diseases.
Neural plasticity has been recognized and studied in relation to pain, and multiple mechanisms have been identified (see Ref. 1 for review). Changes may be rapid and reversible, as for example changes in excitability after exposure of the neurons to sensitizing agents, including prostaglandin E2, 5-hydroxytryptamine, bradykinin, and neurotrophins. Changes may also be longer lasting, and involve increases in expression of transmitters, receptors, or ion channels, or changes in the structure of the neurons themselves. Such long-term changes are seen during inflammation, and include increased expression of tachykinins, the capsaicin receptor VR1, and sensory neuron–specific sodium channels. All these changes may potentiate pain-sensing pathways.
In this issue of the AJRCMB, Kerzel and colleagues report that inhalation of antigen increases capsaicin-induced bronchoconstriction in wild-type mice, but not in mice with a homozygous deletion of p75NTR, one of the neurotrophin receptors (2). This adds to a growing body of literature suggesting that neurotrophins are involved in airway neural plasticity, as has previously been shown in sensory nerves elsewhere.
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Neurotrophins and Neurotrophin Receptors
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The neurotrophins are a family of growth factors that includes nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. Several lines of evidence suggest their involvement in airway disease. Serum NGF levels are elevated in patients with allergic diseases and with asthma (3). Furthermore, exogenous NGF causes airway hyperresponsiveness in guinea pigs (4). NGF-induced hyperresponsiveness is prevented by blocking the substance P receptor (NK-1R), suggesting that tachykinins are involved.
Neurotrophins signal via two sets of receptors. The Trk family of receptor tyrosine kinases bind neurotrophins with high affinity: NGF binds preferentially to TrkA, brain-derived neurotrophic factor and neurotrophin-3 bind to TrkB, and neurotrophin-4 binds to TrkC. In addition, all the neurotrophins bind with similar but lower affinity to a second receptor, p75NTR. This receptor is a member of the tumor necrosis factor superfamily of receptors.
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Complex Effects of Neurotrophins in Neuron Survival and Death
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In general, Trk receptors promote neuron survival, whereas p75NTR promotes cell death. Effector proteins associated with cell death, including caspases, Jun N-terminal kinase, and p53, are all activated by p75NTR (5, 6). These effects may be important in neurodegenerative diseases, as p75NTR is activated by prion protein fragment PrP (26–106) (7), which is neurotoxic, as well as by the Aß peptide of amyloid precursor protein, found in Alzheimer's disease (8). Increased expression of p75NTR may be important in neuron death in amyotrophic lateral sclerosis (9). Furthermore, pro-NGF (which is also secreted) binds with higher affinity to p75NTR and binds poorly to Trk, again favoring cell death (10). However, p75NTR also activates nuclear factor (NF)- B (11), probably via tumor necrosis factor receptor–associated factor-6, and NF-B promotes neuron survival. Furthermore, p75NTR interacts directly with Trk, increasing the binding affinity of Trk for neurotrophins 100-fold (12), and this effect may also promote survival. Thus, the overall effect of neurotrophins on cell survival depends on the receptors present, interactions among receptors, the specific neurotrophin secreted, and the predominant signal transduction pathway activated.
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Neurotrophins in Neural Plasticity
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P75NTR also participates in neural plasticity. Axon elongation is increased by stimulating the p75NTR (13), a result of decreased activation of the small G-protein Rho (which in its active state inhibits elongation via effects on the cytoskeleton). p75NTR can also control axon elongation by interacting with components of myelin and another receptor, the Nogo receptor (14). Neurotrophins also affect synaptic function. p75NTR is involved in neurotrophin-stimulated acetylcholine release by cardiac sympathetic neurons, whereas Trk increases norepinephrine release (15). These effects may be linked to hydrolysis of sphingomyelin, which is stimulated by p75NTR (16). Both Trk and p75NTR increase intracellular calcium (17) and are involved in activity-dependent synaptic plasticity in the hippocampus.
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Changes in Capsaicin Receptors, Tachykinins, and Sodium Channels
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Capsaicin acts on airway sensory nerves by activating vanilloid receptors, causing release of tachykinins. Tachykinins stimulate bronchoconstriction directly, and stimulate gland secretion and epithelial ion transport, mediate neurogenic inflammation, and facilitate synaptic transmission in the nucleus of the tractus solitarius (potentially augmenting airway reflexes [18]). Stimulation of sensory fibers via this receptor may also initiate reflex cholinergic bronchoconstriction (19).
The vanilloid receptor VR1 is a nonspecific cation channel (20). This receptor responds not only to capsaicin, but also to some noxious stimuli, including heat and acid (20). Expression of this receptor is increased in sensory neurons in the presence of inflammation (21). This causes heat hyperalgesia. Inflammation-induced increase in VR1 protein is blocked by antibodies to NGF, and depends on NGF-mediated phosphorylation of p38 (22). NGF also increases the function of existing VR1 receptors (23).
Airway inflammation may also increase the expression of tachykinins in subpopulations of sensory nerve fibers. Under normal circumstances, tachykinins are expressed by small, slow conducting, nonmyelinated C-fibers in the airways. After antigen inhalation (24, 25) or viral infection (26), larger A -fibers, which normally do not express tachykinins, begin to express this class of neurotransmitter (Figure 1). Similar increases in tachykinin expression can be induced by the direct application of NGF to the airway wall (27). These A fibers do not express VR1 receptors, and are not sensitive to capsaicin (25). However, they do respond to touch, and the expression of tachykinins in these fibers has the potential to make the airway respond to touch with tachykinin-mediated responses usually seen after application of capsaicin. Similar changes in somatic sensory nerves lead to the perception of pain in response to touch, a phenomenon known as allodynia.
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Figure 1. Expression of tachykinins in the nodose ganglion of the vagus is increased in antigen challenged guinea pigs. Left panel: immunostaining using an antibody that recognizes substance P and neurokinin A demonstrates positive staining in 48% of ganglion cells 24 h after inhalation of antigen. Right panel: In control animal, only 25% of ganglion cells stain positive for SP/NKA. Scale bar = 50 µM. Reprinted with permission from Ref. 23.
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The ability of inflammatory stimuli to induce expression of tachykinins may not be limited to sensory neurons. Wu and coworkers recently demonstrated that interleukin-1ß can induce expression of tachykinins in the cholinergic neurons of the airway parasympathetic ganglia (28). As interleukin-1ß can induce expression of NGF (29), it is possible that pathways similar to those thought to be important in sensory neurons are also involved in the parasympathetic ganglia.
Sensory nerve expression of the neuron-specific sodium channel SNS is also increased by NGF (30–32). This may increase sodium currents and increase excitability.
Thus, neural plasticity in the inflamed airway might both increase the synthesis of tachykinins and facilitate their release. As conditions causing airway inflammation may also decrease the activity of neutral endopeptidase (33, 34), an enzyme that inactivates tachykinins, the effects of tachykinins may be further potentiated. Airway inflammation also causes loss of function and decreased expression of inhibitory M2 muscarinic receptors on the cholinergic nerves (35). This increases the release of acetylcholine, increasing the reflex bronchoconstriction initiated by hypersensitive sensory nerves.
Thus both afferent and efferent limbs of the reflex are affected by neural plasticity, and may contribute to the increased airway response to capsaicin described by Kerzel and colleagues. NGF may be involved both directly, changing sensory nerve structure and function, and indirectly by promoting airway inflammation.
What is the source of the NGF in this system? Although NGF is produced by a wide variety of tissues, the association of the observed changes with inflammation makes leukocytes attractive candidates. It is widely accepted that airway inflammation is important in the pathogenesis of asthma and other airway diseases. Perhaps more relevant to plasticity of airway nerves is the finding that the airway nerves are inflamed in patients with asthma (36). In patients dying of acute asthma, eosinophils are clustered along the airway nerves (Figure 2), with extracellular eosinophil granule proteins demonstrating that the eosinophils were activated (36). Likewise, in antigen-sensitized guinea pigs and rats, eosinophils are selectively recruited to the airway nerves (Figure 2). Activation of these eosinophils, as occurs after antigen challenge and after viral infections (37), releases proteins that may affect the function of vagal efferents. As activated eosinophils are known to synthesize and release NGF (38), it is tempting to speculate that these eosinophils, or other inflammatory cells in the nerves, mediate the neural plasticity in airway disease.
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Figure 2. Eosinophilic inflammation of the airway nerves in asthma (A and C) and in antigen-challenged guinea pigs (B and D). (A) Eosinophils cluster around an airway nerve bundle in a patient with fatal asthma. Nerves stain black with an antibody to the nerve-specific protein PGP9.5, eosinophils stain red with an antibody to major basic protein. (B) Eosinophils cluster around (and within) a nerve bundle in the airway of an antigen-challenged guinea pig, stained with hematoxylin and eosin. (C) Eosinophils (red) line up along an airway nerve fiber (black) in a patient with fatal asthma. (D) Eosinophils (red) line up along an airway nerve fiber (brown, stained for cholinesterase) in an antigen-challenged guinea pig. Reprinted with permission from Ref. 35.
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Conversely, eosinophils and other leukocytes express receptors for NGF (39). Thus the decrease in airway inflammation in p75NGR-/- mice may have multiple explanations. Lack of response to NGF in leukocytes may inhibit their migration into the airways. Lack of response to NGF in the nerves may decrease the expression and release of tachykinins, which normally may participate in recruitment and activation of inflammatory cells after antigen challenge. Furthermore, deletion of p75NTR is known to decrease somatic sensory innervation (40). It is unknown whether this effect extends to the airway.
Thus, neural plasticity can participate in the functional changes seen in the inflamed airway. Recruitment of inflammatory cells to the airway, and to the nerves themselves, as seen in asthma and in antigen-sensitized animals, provides a source of neurotrophins, which are prime candidates as mediators of neural plasticity. Neurotrophins can increase tachykinin expression in both sensory and cholinergic neurons. Neurotrophins may also increase tachykinin release via multiple effects, including increased VR1 expression and VR1 function, and increased expression of neuronal sodium channels. Studying the mechanisms and consequences of airway neural plasticity will elucidate the links among inflammation, hyperresponsiveness, and asthma.
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Acknowledgments
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This article was funded by NIH HL54659 and HL61013. The author thanks Drs. Allison Fryer and Maureen Horton for comments.
Received in original form December 13, 2002
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Copyright © 2003 American Thoracic Society.
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Introduction
Neurotrophins and Neurotrophin...