Summary
Airway hypersensitivity is a common pathophysiological feature in various airway inflammatory diseases. Increasing evidence suggests that activation of the transient receptor potential vanilloid type 1 receptor (TRPV1) plays an important part in the manifestation of various symptoms of airway hypersensitivity. This mini-review focuses on recent studies that have revealed several potential contributing factors to the increase in TRPV1 sensitivity in pulmonary sensory neurons during airway inflammatory reaction. In addition, chronic allergic airway inflammation induces a pronounced over-expression of TRPV1 in neurofilament-positive pulmonary sensory neurons in nodose ganglia. A better understanding of the mechanisms underlying the increase in sensitivity and/or expression of TRPV1 during acute and chronic airway inflammation should generate the necessary information for developing effective therapeutic interventions to alleviate airway hypersensitivity.
Introduction
Transient receptor potential vanilloid type 1 receptor (TRPV1) is a polymodal transducer, and belongs to the superfamily of TRP ion channels [1]. TRPV1 is a tetrameric membrane protein with four identical subunits, and each subunit contains six transmembrane-spaning domains, which form a non-selective cation channel with a high permeability to Ca2+. Since it was cloned in 1997 [2], the TRPV1 expressed on the sensory nerve terminals has been recognized as “a molecular gateway” to nociceptive sensation in somatic and visceral tissues [3]. In the last several years, the expression of TRPV1 on the sensory nerves in the respiratory tract and its important role in the regulation of the airway function, especially in disease conditions, have been increasingly recognized [4–7].
The involvement of TRPV1 in the manifestation of various symptoms in airway diseases have been extensively discussed in several recent reviews [4,5,7]. This mini-review is intended to focus specifically on more recent findings of the involvements of TRPV1 in the development of airway hypersensitivity associated with inflammatory reactions in the respiratory tract. We will further discuss the mechanisms possibly underlying the up-regulation of TRPV1 sensitivity and expression under these pathophysiological conditions.
TRPV1-expressing sensory nerves in airways
The afferent activities arising from sensory terminals in the lung and airways are conducted primarily by branches of vagus nerves, and project to the nucleus tractus solitarius in the medulla. Among these sensory nerves, TRPV1 is expressed predominantly in non-myelinated (C-fiber) afferents [8], which represent >75% of the afferent fibers in the pulmonary branch of the vagus nerve. One unique feature of these nerves is the extensive co-expression of TRPV1 with certain sensory neuropeptides, namely tachykinins and calcitonin gene-related peptide (CGRP) [9], that are synthesized in the cell bodies of these neurons located in the nodose and jugular ganglia [10]. Another prominent anatomical feature of these sensory nerves is the axonal arborization of their endings that either extend into the space between epithelial cells or form network-like plexus immediately beneath the basement membrane of epithelium [9,11] (Figure 1), suggesting a role of these afferents in regulating the airway responses to inhaled irritants [12,13]. When these TRPV1-expressing nerve endings are activated either by inhaled irritants or endogenous TRPV1 activators (see details in a later section), centrally-mediated reflex responses are elicited, which include reflex bronchoconstriction and mucus hypersecretion via the cholinergic pathway, accompanied by the sensation of airway irritation and urge to cough (Figure 1). In anesthetized animals, it also elicits the classical “pulmonary chemoreflexes”, characterized by the triad of apnea, bradycardia and hypotension [12]. Activation of TRPV1 also triggers Ca2+ influx and release of tachykinins and CGRP from the sensory terminals. These sensory neuropeptides can act on a number of effector cells in the respiratory tract (e.g., smooth muscles, cholinergic ganglia, mucous glands, immune cells), and elicit the local “axon reflexes” such as bronchoconstriction, protein extravasation and inflammatory cell chemotaxis [10] (Figure 1). These actions generated by tachykinins and CGRP have been well documented in rodents, but the degree of their relative importance in human airways remains to be fully established [10,13].
Figure 1.
Schematic illustration of the function of TRPV1-expressing sensory nerves and their interaction with other cell types in airway mucosa. EO, eosinophil; LO, lipooxygenase; PGE2, prostaglandin E2; BK, bradykinin; NGF, nerve growth factor; MBP, major basic proteins derived from eosinophil degranulation; TKs, tachykinins; CGRP, calcitonin gene-related peptide. See text for details. (Adapted from reference 13)
Airway hypersensitivity: plasticity of TRPV1 in airway diseases
Airway hypersensitivity, characterized by exaggerated sensory (e.g., airway irritation, dyspnea, etc.) and reflexogenic responses (e.g., cough, bronchoconstriction, etc.) to inhaled irritants and certain endogenously released mediators, is a common pathophysiological feature in patients with airway inflammatory diseases such as asthma, bronchitis, viral infection, etc. Increasing and compelling evidence reported in recent studies suggests that the TRPV1 channel plays a pivotal role in the manifestation of various symptoms of airway hypersensitivity in these patients [4,5]. For example, cough sensitivity to TRPV1 activators, capsaicin or citric acid aerosol, was markedly elevated in patients with asthma or airway inflammation [14,15]. Endogenous TRPV1 activators such as H+ and lipooxygenase metabolites are consistently detected in the bronchoalveolar lavage fluid, sputum and/or exhaled breath condensate of patients with inflammatory airway diseases [5]. In addition, certain endogenous inflammatory mediators (e.g., prostaglandin E2, bradykinin, etc.), though not a TRPV1 activator themselves, can markedly enhance the sensitivity of TRPV1 and lower its threshold for activation [5]. Furthermore, cough sensitivity to acute inhalation challenge of ovalbumin aerosol was elevated in sensitized guinea pigs, and the enhanced response was significantly attenuated by TRPV1 antagonists, suggesting the involvement of TRPV1 in the airway hypersensitivity induced by chronic allergic inflammation [16]. Recent studies further revealed that the increased TRPV1-mediated responses is associated with increased expression of the TRPV1 channel in bronchopulmonary sensory nerves in certain chronic airway diseases [17,18]. These observations collectively suggest that plasticity of TRPV1 develops upon the action of various inflammatory mediators and cytokines during airway inflammatory reaction. Either an enhanced sensitivity or an increase in expression of TRPV1, a given level of stimulation is expected to evoke a greater afferent discharge of the TRPV1-expressing sensory nerves in the airways, and consequently more severe sensory and reflex responses, resulting in airway hypersensitivity.
Increased sensitivity of TRPV1
The sensitivity of TRPV1 can be elevated by the actions of a number of chemical, physical and biological factors, as discussed in details in several comprehensive reviews [1,3,4–6]. In this mini-review, we will focus our attention on three of these factors because recent investigations have revealed new information about their involvements in the development of airway hypersensitivity associated with airway inflammatory reaction.
Increase in airway temperature
Tissue inflammation is known to lead to local hyperemia and an increase in temperature in the inflamed area. A recent study reported that the end-expiratory temperature plateau was 2.7°C higher in mild allergic asthmatic children than in healthy children, and the difference was closely correlated with the exhaled nitric oxide concentration as well as the sputum eosinophil percentage [19]. An earlier study in adult patients also showed a faster rise of exhaled temperature in asthmatics than matching controls [20]. These findings seem to suggest that exhaled breath temperature is related to the degree of airway inflammation in asthma.
The four subtypes of TRPV channels, TRPV1–4, are generally considered as the primary sensors for warm and hot temperatures in mammalian species, and each is activated in a different temp range (> 43°C for TRPV1; > 52°C for TRPV2; > 34–38 °C for TRPV3; > 27–35 °C for TRPV4) [21]. A recent study has demonstrated the expression of both mRNA and receptor proteins of all these four subtypes of TRPVs in the cell bodies of sensory neurons innervating the lung structures in rats [22]. These neurons isolated in primary culture also exhibit distinct temperature sensitivity in whole-cell patch-clamp electrophysiological recording experiments [22]. When the temperature was raised from normal (~36°C) to hyperthermic (~40.6°C) level of the rat body temperature and held constant, the inward currents evoked by capsaicin and 2-aminoethoxydiphenyl borate (2-APB), a non-selective activator of TRPV1–3 receptors, were both significantly increased [23]. This potentiating effect was clearly present even at a moderate level of hyperthermia (~39°C). However, it was largely attenuated by selective TRPV1 antagonists, capsazepine or AMG 9810 [23], and completely absent in pulmonary nodose/jugular neurons isolated from TRPV1-null mice [24], suggesting the possible involvement of a positive interaction between hyperthermia and these chemical activators at the TRPV1 channel. Surprisingly, although hyperthermia also potentiated the TRPV1-mediated response to H+, it inhibited the responses mediated through the acid sensing ion channels [23]. The specific site(s) and mechanism underlying this interaction are not known, but an involvement of cytoplasmic COOH-terminal domain of the TRPV1 receptor in the conformational changes has been suggested [25]. Furthermore, in a recent study Voets et al. [26] have clearly demonstrated that increasing temperature to 42°C shifted the TRPV1 channel activation curve (open probability vs. voltage) from a non-physiological positive voltage range towards the negative potential (Figure 2). This large shift of voltage-dependent activation curve to a physiologically relevant voltage range with a relatively small gating charge may explain in part the hyperthermia-induced hypersensitivity in pulmonary sensory neurons expressing the TRPV1 [26,27]. This positive interaction between hyperthermia and chemical activators of TRPV1 is particularly relevant because an increase in tissue temperature during inflammatory reaction may occur concurrently with the release of several endogenous TRPV1 activators such as proton, polycations and certain lipoxygenase metabolites of arachidonic acid (e.g., 12S- and 15S-hydroperoxyeicosatetraenoic acid) in the airways [5].
Figure 2.
Voltage shifts of TRPV1 activation curves by temperature and capsaicin. A, voltage dependence of the open probability of TRPV1 channels at 17°C (triangles) and 42°C (circles). The inset shows the respective current families obtained from a voltage-step protocols (holding potential 0 mV, voltage steps of 100-ms duration from −120 to +160 mV in 40-mV increments). Note the leftward shift of the activation curve towards negative potentials by increasing the temperature. B, the same voltage protocol as in A, and the temperature was held at 24°C. Activation of TRPV1 by capsaicin (100 nM; circles) also caused a pronounced leftward shift of the activation curve. (Adapted from reference 27)
Protease-activated receptors-2 (PAR2)
PAR2 belongs to a family of G-protein-coupled, seven-transmembrane-domain receptors named PARs that are uniquely activated by proteolysis [28]. PAR2 activation occurs after cleavage of its extracellular N-terminal domain by specific proteases, revealing a new N-terminus that acts as a tethered ligand binding to and activating the receptor (Figure 3). Expression of PAR2 has been demonstrated in a variety of cells in the lung and airways, including TRPV1-positive sensory neurons [29]. Mast cell tryptase, trypsin and trypsin-like proteases, and coagulation factors VIIa and Xa are considered as the endogenous agonists of PAR2 [29,30]. PAR2 can also be activated by certain airborne allergens such as house dust mite Der P1, P3 and P9 [31]. In addition, tissue kallikreins, a large family of secreted serine proteases with tryptic or chymotryptic activity, are recently proposed as physiological regulators of PAR2 [32].
Figure 3.
Schematic illustration of the hypothesized interaction between PAR2 and TRPV1 in pulmonary sensory neurons. PAR2, protease-activated receptor-2; FVIIa, coagulation factor VIIa; FXa, coagulation factor Xa; PAR2-AP, synthetic PAR2 activating peptide; TM, transmembrane domain; Gq/11 and Gs, G proteins; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-triphosphate; DAG, diacylglycerol; PKC, protein kinase C; [Ca2+]i, intracellular Ca2+ concentration; TKs, tachykinins; AC, adenylate cyclase; PKA, protein kinase A; PGE2, prostaglandin E2, IL, interleukin. See text for details.
Compelling evidence indicates that PAR2 plays a critical role in the pathogenesis of airway inflammation and airway hyperresponsiveness. The elevated levels of both the endogenous agonists and the expression of PAR2 have been reported from patients and animals under airway inflammatory conditions [30,33]. Activation of PAR2 in the lung induces airway constriction, lung inflammation, and protein-rich pulmonary edema [34–36]. These effects are inhibited by either perineural capsaicin treatment of both vagi or the combination of neurokinin-1 (NK1), NK2 and CGRP receptor antagonists, indicating the involvement of neuropeptides released from TRPV1-containing C-fiber afferents. Indeed, a recent study showed that PAR2 activation up-regulates the excitability of rat pulmonary chemosensitive neurons and potentiate the capsaicin-induced, TRPV1-mediated pulmonary chemoreflex responses [37]. PAR2 activation also exaggerates the TRPV1-dependent tussive response in guinea pigs [38]. Furthermore, PAR2 activation is often associated with release of various proinflammatory mediators including prostanoids such as prostaglandin E2, and cytokines such as interleukin (IL)-6 and IL-8 [29,39,40]. These mediators are known to have potential regulatory effects on the sensitivity of TRPV1 [5].
The signaling mechanisms of PAR2 are not fully understood. In a number of cell systems, PAR2has been reported to be coupled to Gq/11 protein to activate phospholipase C, resulting in generation of second messengers, inositol 1,4,5-triphosphate and diacylglycerol, which further trigger mobilization of Ca2+ and activation of protein kinase C [28]. Involvements of PKC, PKA and possibly PKD have recently been proposed in PAR2-induced sensitization of TRPV1 as well as other TRP channels in sensory neurons [37,41–43] (Figure 3).
Polycations
Recent studies have reported that extracellular cations such as Mg2+ and Ca2+ can sensitize and gate TRPV1 [44]. A similar effect can also be generated by polyamines (such as spermine, spermidine and putrescine), the organic polycations that are known to modulate inflammation and nociception [45]. More importantly, it has been reported that the blood levels of these polyamines were significantly elevated in patients during asthmatic attack [46]. The study by Ahern et al. further suggested that the extracellular acidic residues ASP-646 and Glu-648, which are located near the pore-forming region of TRPV1, play an important role in polyamine regulation. Their hypothesis was supported by the finding that spermine failed to increase the whole-cell current evoked by protons in TRPV1-expressing oocytes [45].
Airway infiltration of eosinophils and the release of their granule-derived, low molecular weight and highly cationic proteins (i.e., major basic protein, eosinophil cationic protein, eosinophil peroxidase and eosinophil-derived neurotoxin) occur in a variety of airway inflammatory diseases including asthma [47]. Furthermore, the increases in both the number of eosinophils and levels of eosinophil-derived cationic proteins in the bronchoalveolar lavage fluid of asthmatic patients are correlated with the severity of the disease [48]. Recent studies have demonstrated that these eosinophil-derived cationic proteins can directly sensitize the capsaicin-evoked, TRPV1-mediated whole-cell responses in isolated rat pulmonary sensory neurons; the effect of these proteins was completely abolished when their cationic charges were neutralized by mixing with a polyanion [49]. Whether these eosinophil granule proteins increase the sensitivity of TRPV1 via a similar mechanism as polyamines remains to be determined.
Over-expression of TRPV1 in chronic airway inflammation
In addition to increased excitability of the channel, an increase in the TRPV1 receptor protein expression can also contribute to the airway hypersensitivity, particularly in chronic airway diseases. For example, the TRPV-1 immunoreactive nerve profile was five-fold higher in the biopsies of bronchial tissue from patients with chronic cough than healthy individuals [17]. Furthermore, there was a significant correlation between the cough sensitivity to capsaicin inhalation challenge and the density of TRPV1-expressing nerves in the mucosa of patients with chronic cough [17,50]. These observations have provided strong evidence to suggest an increase in expression of TRPV1 in the sensory endings of airway mucosa may be involved in the development of chronic cough. A recent study showed that, after chronic airway inflammation was induced by allergen sensitization, capsaicin evoked a pronounced stimulatory effect on vagal bronchopulmonary myelinated afferents, which normally exhibit no or very little sensitivity to capsaicin [18]. Immunohistochemical experiments further indicated a pronounced increase in the proportion of TRPV1-expressing bronchopulmonary neurons in nodose ganglia of sensitized rats, and the increased TRPV1 expression was found mainly in neurofilament-positive neurons (myelinated neurons) [18]. This observation is in general agreement with another recent finding of an increased number of TRPV1- immunoreactive axons within the tracheal epithelium and around smooth muscles of ovalbumin-sensitized guinea pigs by Watanabe et al. [51]. The mechanism underlying the phenotypic change in TRPV1 expression in pulmonary myelinated neurons was not known. However, a possible involvement of neurotrophins such as brain-derived neurotrophic factor and nerve growth factor should be considered. These neurotrophins are known to up-regulate the expression of TRPV1 in sensory neurons [52,53,54,55], or promote translocation of the TRPV1 to cell membrane [56], and their synthesis and release have been shown to increase in allergic airways [57,58].
Conclusion
Airway hypersensitivity is a common and debilitating problem for patients with various airway inflammatory diseases. Cumulative evidence indicates that TRPV1 plays a key part in the manifestation of various symptoms of airway hypersensitivity, suggesting that TRPV1 is an important target for pharmacological interventions. To obtain the necessary information for developing new effective therapeutic strategy, further investigations on the mechanisms involved in the increase in sensitivity and/or expression of TRPV1 during both acute and chronic airway disease conditions are required. In addition, it is evident that the interaction between TRPV1 and other ion channels and regulatory receptor proteins that are also expressed on these airway sensory nerves is important in modulating the function of airway sensory neurons. Thus, TRPV1 functions not only as a transducer, but also an integrator of multiple endogenous activators and modulatory molecules. A better understanding of the overall role of TRPV1 in regulating the excitability of these neurons during airway inflammatory reaction is probably one of the most important steps in uncovering the underlying mechanism of airway hypersensitivity.
Acknowledgments
The work was supported in part by USPHS grants from the National Institutes of Health (HL58686 to L.-Y.L.; AI76714 to Q.G.).
Footnotes
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