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INFLAMMATION AND IMMUNOPHARMACOLOGY
Center of Excellence for the Study of Inflammation, University of Ferrara, Ferrara, Italy (M.T., D.G., F.B., B.C., M.R., S.H.); Clinical Research Unit of Allergy, Charité School of Medicine, Berlin, Germany (Q.T.D., D.A.G., A.F.); Sanofi Recherche, Montpellier, France (X.E.-A.); CEA, Service de Pharmacologie et d'Immunologie, CEA-Saclay, Gif sur Yvette, France (C.C.); and Department of Critical Care Medicine and Surgery, University of Florence, Florence, Italy (P.G.)
Received December 11, 2003; accepted February 4, 2004.
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Abstract |
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). We recently demonstrated a novel excitatory activity of EtOH (Trevisani et al., 2002) in a specific subset of neurons that are sensitive to the excitatory action of capsaicin and that contain neuropeptides, including the calcitonin gene-related peptide (CGRP) and the tachykinins, substance P (SP) and neurokinin A (Holzer, 1991). Stimulation of these peptidergic C- and A
-fibers results in the activation of nociceptive and protective reflex responses, as well as the release of neuropeptides from their peripheral endings. This latter effect causes a series of local inflammatory responses collectively referred to as "neurogenic inflammation," which in the airways include plasma extravasation and bronchoconstriction (Holzer, 1991; Geppetti and Holzer, 1996).
The unique sensitivity of primary sensory neurons to capsaicin and other vanilloid molecules (Szallasi and Blumberg, 1999) is conferred by the expression on the neuronal plasma membrane of the vanilloid receptor-1 (Caterina et al., 1997), a nonselective cation channel belonging to the transient receptor potential (TRP) family, and for this reason reclassified as transient receptor potential vanilloid-1 (TRPV1) (Gunthorpe et al., 2002). Additional stimuli that can activate TRPV1 are temperature (>43°C) (Caterina et al., 1997), low pH (pH 6-5) (Geppetti et al., 1991), and lipid derivatives, including anandamide (AEA) (Zygmunt et al., 1999; Smart et al., 2000; Tognetto et al., 2000), 12-hydroperoxyeicosatetraenoic acid, leukotriene B4 (Hwang et al., 2000) and N-arachidonyldopamine (Huang et al., 2002). EtOH has been found to potentiate dramatically the action of various agents known to stimulate the TRPV1, including protons and AEA (Trevisani et al., 2002). More importantly, EtOH lowers the threshold of TRPV1 activation by temperature, so that at the physiological temperature (37°C) exposure to EtOH (0.3-3%) activates a TRPV1-dependent current, increasing intracellular Ca2+mobilization, inducing release of sensory neuropeptides from dorsal spinal cord, and causing neurogenic plasma extravasation in the esophagus (Trevisani et al., 2002).
EtOH ingestion is considered to trigger asthma attacks in susceptible individuals (Myou et al., 1996; Saito et al., 2001). The EtOH metabolite acetaldehyde (AcH) is considered to play a major role in this effect of EtOH, evoking bronchoconstriction both in rodents (Bianchi et al., 1998; Koivisto et al., 1999) and humans (Fujimura et al., 1999), through the release of histamine from mast cells (Myou et al., 1995; Shimoda et al., 1996). There is evidence that a minor component of bronchoconstriction and plasma extravasation caused by AcH is due to a neurogenic inflammatory mechanism, e.g., sensory nerve terminal stimulation and the subsequent release of SP and neurokinin A (Berti et al., 1994).
The novel findings reported above (Trevisani et al., 2002) that EtOH stimulates sensory nerves via TRPV1 activation suggests that EtOH might per se cause neurogenic inflammatory responses in the airways. Thus, in the present study we have explored the possibility that EtOH activates TRPV1 in guinea pig airway sensory nerves and in this manner causes inflammatory neurogenic responses. To accomplish this purpose, we investigated the ability of EtOH, in airway tissue, to cause via TRPV1 activation: release of CGRP and SP, contraction of isolated airways in vitro, bronchoconstriction, and plasma protein extravasation in vivo.
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Materials and Methods |
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Release Assay. Guinea pigs were terminally anesthetized and decapitated. The airways (including trachea and bronchus) were prepared at 4°C using a tissue slicer (McIlwain tissue chopper; Mickle Laboratory Engineering Co. Ltd, Surrey, UK). Slices (
100 mg) were placed in 2-ml chambers and superfused at 0.4 ml/min with a Krebs' solution of the following composition: 119 mM NaCl, 25 mM NaHCO3, 1.2 mM KH2PO4, 1.5 mM MgSO4, 2.5 mM CaCl2, 4.7 mM KCl, and 11 mM D-glucose. To the basic Krebs' solution the following agents were added: 0.1% bovine serum albumin and 1 µM phosphor-amidon, maintained at 37°C, and gassed with 95% O2 and 5% CO2. After a 90-min stabilization period, 10-min fractions were collected into acetic acid (final solution 2 N). Two prestimuli samples were taken at 10-min intervals followed by a third set of samples during stimulation. A final poststimulus 10-min sample was also collected. At the end of the experiment, tissues were blotted and weighed. Fractions were freeze-dried, reconstituted with assay buffer, and analyzed by enzyme immunoassays for CGRP-LI and SP-LI according to the methods reported previously (Frobert et al., 1999; Ricciardolo et al., 2000). The detection limits of the assays were 5 pg/ml CGRP and 2 pg/ml SP. The level of release of CGRP-LI and SP-LI were calculated by subtracting the mean prestimulus value from those values obtained during and poststimulation. The results are expressed as femtomoles of peptide per gram per tissue per 20 min. The highest concentration of EtOH (3%), capsaicin (10 µM), and CPZ (10 µM) did not show any significant cross-reactivity with CGRP and SP antisera.
Organ Bath Studies. Guinea pigs were sacrificed by cervical dislocation, and the lungs were removed and rings from the main bronchi (approximately 2 mm in width) were suspended with a resting tension of 1.5 g. The tissues were bathed and aerated (95% O2 and 5% CO2) with Krebs' solution (see above), which was maintained at 37°C and contained phosphoramidon (1 µM) to minimize peptide degradation. Tissues were allowed to equilibrate for 60 min before the beginning of and between each set of experiments (washed every 5 min). In all experiments, the tissues were first contracted with carbachol (CCh; 1 µM).
Cumulative concentration-response curves were performed with EtOH (0.01-10%), AcH (0.01-3%), capsaicin (0.01 nM-1 µM), and SP (0.01 nM-1 µM), either in the presence of the selective TRPV1 antagonist CPZ (10 µM), the combination of the selective tachykinin NK1 (SR 140333; 1 µM) (Emonds-Alt et al., 1993) and NK2 (SR 48968; 1 µM) (Emonds-Alt et al., 1992) receptor antagonists, nonselective muscarinic antagonist atropine (1 µM), the cyclooxygenase inhibitor indomethacin (5 µM), nitric-oxide synthase inhibitor N
-nitro-L-arginine methyl ester (L-NAME; 100 µM), or their respective vehicles.
In another set of experiments, bronchial preparations were preincubated twice for 20 min with a capsaicin (10 µM) concentration known to desensitize the sensory nerve endings (Szallasi and Blum-berg, 1999). The bathing fluid was then changed repeatedly (every 5 min over a period of 1 h) until the contractile response had returned to baseline, and cumulative concentration-response curves were performed with EtOH or the other agents.
In Vivo Bronchoconstriction. Guinea pigs were anesthetized with sodium pentobarbital (60 mg/kg i.p.) and ventilated artificially through a tracheal cannula at a frequency of 60 breaths/min. Airflow was monitored continuously with a pneumotachograph (A Fleisch Medical Inc., Richmond, VA) connected to a differential pressure transducer (model DP45; Validyne, Northridge, CA), according to the method reported previously (Ricciardolo et al., 2000). The right jugular vein was cannulated for drug administration. The values are expressed as the percentage increase over the basal level. Bronchoconstriction was provoked by a single administration of EtOH (221 mg/kg i.v. or 790 mg/kg intragastric), capsaicin (25 nmol/kg i.v.) or SP (0.1 nmol/kg i.v.). These experiments were also performed in the presence of CPZ (10 µmol/kg i.p.) given 10 min before the stimulus.
Plasma Extravasation. Guinea pigs were anesthetized with sodium pentobarbital (60 mg/kg i.p.). Evans blue (30 mg/kg) was injected into the jugular vein and 1 min later an instillation of EtOH was performed. After 5 additional minutes, animals were transcardially perfused. Pretreatment with SR 140333 (1 mg/kg i.v.), CPZ (0.1 mM, 100 µl i.t.), or their respective vehicles were given 15 min before the injection of the dye. The trachea was removed, weighed, and incubated in 1 ml of formamide for 24 h in the dark, at room temperature. The amount of extravasated Evans blue was measured spectrophotometrically at 620 nm.
Chemical Reagents. Drugs and reagents were obtained from the indicated companies: EtOH, AcH (Carlo Erba Reagent, Milano, Italy); atropine, bovine serum albumin, capsaicin, capsazepine, CCh, indomethacin, L-NAME, phosphoramidon, SP (Sigma-Aldrich, Milan, Italy); SR 140333 and SR 48968 were synthesized at Sanofi-Synthelabo (Montpellier, France). All drugs were dissolved in saline with the exception of capsaicin, CPZ, and indomethacin that were stocked at a concentration of 1 mM in DMSO (100%) with further solution dissolved in saline.
Statistical Analysis. All data are mean ± standard error of the mean. Contractile responses in vitro are expressed as a percentage of the response to CCh (1 µM). Statistical analysis was performed by means of the Student's t test or analysis of variance and the Dunnett's test when required (Glantz, 1992). If P < 0.05, the results were considered significant.
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Results |
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In Vitro Airway Constriction Induced by EtOH, AcH, Capsaicin, CCh, and SP. Exposure to EtOH (0.01-10%) on guinea pig isolated bronchi caused a concentration-related contraction. Threshold concentration to cause a visible contractile effect was 0.1 to 0.3% and maximum response (97 ± 7% of CCh) was obtained with 3% EtOH (Figs. 2A and 3A). The contractile effect of EtOH was significantly attenuated by capsaicin pretreatment (preincubated twice for 20 min with a capsaicin concentration of 10 µM) or by a combination of tachykinin NK1 and NK2 (SR 140333 and SR 48968 both at 1 µM, respectively) receptor antagonists (Figs. 2B and 3A). A small component of the contraction resistant to both capsaicin pretreatment and tachykinin antagonists was seen at 3% EtOH. Thus, this residual component of the contraction is probably not mediated by sensory nerve activation (Fig. 3A). CPZ (10 µM) shifted to the right the concentration-response curve to EtOH (Fig. 3A): the response to 1% EtOH was practically abolished and the response to 3% EtOH was halved by CPZ. Capsaicin (0.01 nM-1 µM), SP (0.01 nM-1 µM), and CCh (0.01 nM-100 µM) induced a concentration-related contraction of isolated guinea pig bronchi (Fig. 2C). The concentration-response curve to capsaicin was shifted to the right by CPZ, whereas the one to SP was not (data not shown), indicating specificity by CPZ. Pretreatment with EtOH (3%) caused a marginally and not significant reduction in the contractile response to capsaicin (not shown). The possible role of prostanoids, cholinergic, and nitrergic mechanisms on airway constriction produced by EtOH was ruled out, because indomethacin (5 µM), atropine (1 µM), and L-NAME (1 µM) did not affect the contractile response to EtOH (not shown).
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AcH (0.01-3%) contracted the isolated guinea pig bronchus in a concentration-related manner (Figs. 2A and 3B). Threshold concentration of AcH to produce this effect was 0.03% and maximum response was obtained with 1%. AcH was about 3 times more potent than EtOH to contract the guinea pig isolated bronchus. However, in contrast with EtOH, airway constriction in response to AcH was marginally reduced by capsaicin pretreatment only when the highest concentration of AcH was used (Figs. 2B and 3B), thus indicating that sensory nerve activation plays, if any, a minor role in the motor response to AcH. Tachykinin receptor antagonists (1 µM) and CPZ (10 µM) were also ineffective in reducing the airway constriction evoked by AcH (Fig. 3B), thus strengthening the proposed hypothesis.
In Vivo Bronchoconstriction. After a stabilization period of 30 min, baseline bronchoconstriction remained stable for at least 2 h. Injections (1 ml/kg i.v. or intragastric) of the vehicle of EtOH (0.9% NaCl) did not change the baseline value of bronchoconstriction. The intravenous injection of 221 mg/kg EtOH produces a statistically significant increase in pulmonary insufflation pressure (PIP) (Fig. 4A). This response to EtOH (389 ± 55% of baseline value; n = 5) was markedly reduced by a dose of CPZ (10 µmol/kg i.p., 149 ± 32% of baseline value; n = 6, P < 0.05) (Fig. 4A) that inhibited the bronchoconstrictor response to capsaicin (25 nmol/kg i.v.) but did not alter the response to SP (0.1 nmol/kg i.v.) (Fig. 4A). These finding clearly indicated selectivity of this dose of CPZ for capsaicin-induced response and hence for the TRPV1.
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In a second series of experiments, EtOH was given by an intragastric route of administration to mimic the route through which alcoholic beverages are used. EtOH (790 mg/kg, administered via a cannula that reached the gastric cavity) significantly increased PIP (104 ± 25%; n = 6) compared with the injection of its vehicle (0.9% saline, 1 ml/kg, 5 ± 3%; n = 5, P < 0.01). The bronchomotor response to intragastric EtOH (790 mg/kg) was observed in the presence of CPZ vehicle (108 ± 24%; n = 5) was markedly decreased by pretreatment with CPZ (10 µmol/kg i.p, 24 ± 8%; n = 5, P < 0.05) (Fig. 4B).
Plasma Extravasation. Baseline Evans blue extravasation in the guinea pig trachea after the injection of vehicle of EtOH (280 µl/kg of 0.9% saline) was 14 ± 2 ng/g tissue. The injection of 221 mg/kg EtOH produce a statistically significant increase in Evans blue extravasation (39 ± 7%; n = 6) (Fig. 5A), a response that was abated by CPZ (10 µmol/kg i.p., 18 ± 5%; n = 6). This dose of CPZ blocked the increase in Evans blue caused by capsaicin (25 nmol/kg i.v.) but did not alter the response to SP (0.1 nmol/kg i.v.) (Fig. 5A). As in the case of the bronchoconstriction studies, these finding indicated selectivity of CPZ for capsaicin-induced responses and hence for the TRPV1.
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Intragastric administration of EtOH vehicle (1 ml/kg of 0.9% saline, administered via a cannula that reached the gastric cavity) caused an extravasation of the Evans blue dye that was 16 ± 4 ng/g of tissue (n = 4) in the guinea pig trachea. Intragastric EtOH (790 mg/kg) administration in the presence of CPZ vehicle significantly increased the extravasation of the Evans blue dye (41.1 ± 4.9%; n = 10), an effect that was markedly decreased in the presence of CPZ (20.9 ± 4%; n = 7) (Fig. 5B).
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Discussion |
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However, the most remarkable observations of the present study are those related to functional in vitro and in vivo experiments. Concentrations of EtOH identical to those used in the peptide release experiments produced a marked contraction of isolated guinea pig bronchi. It is worth mentioning that the efficacy of EtOH to contract the isolated guinea pig bronchi paralleled those of powerful spasmogenic substances, such as CCh or SP. Several lines of evidence show that the mechanism of EtOH-induced bronchoconstriction is neurogenic. First, the response to EtOH was abolished by pretreatment with an elevated concentration of capsaicin, a procedure known to selectively defunctionalize sensory nerves (Szallasi and Blumberg, 1999). Second, this response was abolished by a combination of NK1 and NK2 receptor antagonists, indicating that tachykinins release from sensory nerves were involved. Also, in the case of in vitro bronchoconstriction experiments, a large part of the excitatory effect of EtOH was due to TRPV1 activation because the response to EtOH was diminished by CPZ, at a concentration that left unchanged the contraction produced by SP, thus indicating selectivity.
AcH is a known bronchoconstrictor agent for rodents (Bianchi et al., 1998; Koivisto et al., 1999) and humans (Fujimura et al., 1999). This effect of AcH is apparently mediated by histamine release from mast cells (Myou et al., 1995; Shimoda et al., 1996). There is evidence (Berti et al., 1994) that at least a minor part of AcH proinflammatory action in the airways is mediated by sensory nerve activation. In the present in vitro experiments, AcH produced a remarkable bronchial contraction, being as efficacious as, and slightly more potent than, EtOH. These findings suggest that the contraction produced by EtOH could result from the bronchoconstrictor action of AcH produced locally from the metabolism of EtOH. However, different observations reject this hypothesis. In contrast to EtOH, the contractile effect of AcH was marginally reduced by capsaicin desensitization and unaffected by tachykinin receptor antagonists and CPZ, indicating that this action was non-neurogenic and TRPV1-independent and that the mechanism of AcH differs from that of EtOH. Although specific investigation in the guinea pig airways is lacking, a recent study in the dog showed that, contrary to the liver parenchyma, in the trachea no alcohol dehydrogenase could be found (Maier et al., 1999), thus strengthening the hypothesis that AcH is not produced from EtOH in the airways.
Finally, we showed that two major in vivo proinflamma-tory responses, such as bronchoconstriction and plasma extravasation, are produced in the guinea pig airways by EtOH via a neurogenic mechanism. The role of TRPV1 in EtOH-induced bronchoconstriction and plasma extravasation is indicated by the ability of CPZ to selectively abolish these responses. Thus, if sufficient amounts of EtOH are present in the airways they may activate TRPV1 on terminals of primary sensory neurons and produce neurogenic inflammatory responses.
There is a report showing a minor fall in sGaw and increase in pulse rate in a few asthma patients (Ayres and Clark, 1982). These effects were possibly ascribed to stimulation of irritant receptors in the upper airways (Ayres and Clark, 1982). In contrast, another study did not demonstrate any significant effect on upper airway reflex sensitivity (Erskine et al., 1994). Irrespective of these findings, the majority of studies point to the fact that alcoholic beverages on average exacerbate asthma (Cuddy and Li, 2001). Furthermore, alcoholic beverages are known to trigger a wide range of allergic responses (rhinitis, headache, cough, and asthma) (Vally and Thompson, 2002). The sensitivity of EtOH to trigger those adverse effects (particularly among the Asian population) is partly due to a reduced capacity to metabolize AcH (Vally and Thompson, 2003). In addition, other molecules contained in certain alcoholic beverages, such as sulfite additives and histamine (a by-product of the fermentation process of red wine) are thought to be contributing factors in wine-based alcohol-induced asthma (Vally and Thompson, 2002). Nevertheless, the present observation that EtOH per se is able to induce inflammatory responses in a rodent airway model relevant for human asthma suggests that this novel mechanism may also contribute to alcohol-induced asthma. Of particular interest is the observation that in guinea pigs an intragastric dose of EtOH as low as 790 mg/kg can cause two effects, bronchoconstriction and airway edema, which are particularly relevant for asthma. It is worth mentioning that 790 mg/kg EtOH corresponds to amounts of alcohol not infrequently assumed for alimentary or recreational uses, such as a half liter of wine or two to three glasses of whiskey.
The clinical finding that the threshold concentration of capsaicin to induce cough is lowered in asthma (Doherty et al., 2000; Barber et al., 2001) suggests the hypothesis that chronic inflammation may up-regulate or "sensitize" TRPV1.In a patient with a chronic inflammatory process in the airways, a possible sensitized TRPV1 could be more responsive to endogenous and exogenous stimuli, including EtOH and could cause exaggerated inflammatory airway responses. In human embryonic kidney cells transfected with the human TRPV1, relatively moderate concentrations of EtOH have been demonstrated to potentiate the response of TRPV1 to stimuli such as capsaicin, protons, and heat (Trevisani et al., 2002). Much uncertainty, however, exists regarding the mechanisms that eventually result in TRPV1 "up-regulation/sensitization". Bradykinin B2 receptor activation have been proposed to activate TRPV1 via 1) protein kinase C-
and channel phosphorylation (Cesare et al., 1999); 2) a phospholipase C-dependent displacement of inositol bisphosphates from TRPV1 binding (Chuang et al., 2001); or 3) the release of 12-hydroperoxyeicosatetraenoic acid (Hwang et al., 2000). It is worth mentioning that both kinins (Bertrand and Geppetti, 1996; Proud, 1998) and nerve growth factor in the serum (Bonini et al., 1999) and airways (Kassel et al., 2001) are increased in asthma and seem to play a major role in this disease. It would be of interest to explore the role of these molecular mechanisms in the regulation of TRPV1 in in vivo conditions and especially in asthma.
A better understanding of the mechanisms by which inflammatory mediators regulate intracellular pathways in sensory neurons, and possibly TRPV1 sensitization, may also clarify the concentrations of EtOH required to trigger neurogenic inflammatory responses in different organs including the airways.
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Footnotes |
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ABBREVIATIONS: EtOH; ethanol; CGRP, calcitonin gene-related peptide; SP, substance P; TRP, transient receptor potential; TRPV1, transient receptor potential vanilloid-1; AcH, acetaldehyde; CPZ, capsazepine; CCh, carbachol; L-NAME, N-nitro-L-arginine methyl ester; NK, neurokinin; DMSO, dimethyl sulfoxide; PIP, pulmonary insufflation pressure; SR 140333, nolpitantium; SR 48968, (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide.
1 These authors contributed equally to this study. 
Address correspondence to: Dr. Selena Harrison, Center of Excellence for the Study of Inflammation, University of Ferrara, 44100 Ferrara, Italy. E-mail: selena.harrison{at}unife.it
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