S-CMC-Lys-dependent stimulation of electrogenic glutathione secretion by human respiratory epithelium.

Glutathione (GSH) is one of the most important defense mechanisms against oxidative stress in the respiratory epithelial lining fluid. Considering that GSH secretion in respiratory cells has been postulated to be at least partially electrogenic, and that the mucoregulator S-carbocysteine lysine salt monohydrate (S-CMC-Lys) can cause an activation of epithelial Cl(-) conductance, the purpose of this study was to verify whether S-CMC-Lys is able to stimulate GSH secretion. Experiments have been performed by patch-clamp technique, by high-performance liquid chromatography (HPLC) assay, and by Western blot analysis on cultured lines of human respiratory cells (WI-26VA4 and CFT1-C2). In whole-cell configuration, after cell exposure to 100 microM S-CMC-Lys, a current due to an outward GSH flux was observed, which was inhibitable by 5-nitro-2-(3-phenylpropylamino)-benzoate and glibenclamide. This current was not observed in CFT1-C2 cells, where a functional cystic fibrosis transmembrane conductance regulator (CFTR) is lacking. Inside-out patch-clamp experiments (GSH on the cytoplasm side, Cl(-) on the extracellular side) showed the activity of a channel, which was able to conduct current in both directions: the single channel conductance was 2-4 pS, and the open probability (P(o)) was low and voltage-independent. After preincubation with 100 microM S-CMC-Lys, there was an increase in P(o), in the number of active channels present in each patch, and in the relative permeability to GSH vs Cl(-). Outwardly directed efflux of GSH could also be increased by protein kinase A, adenosine 5'-triphosphate, and cyclic adenosine monophosphate (cAMP) added to the cytoplasmic side (whole-cell configuration). The increased secretion of GSH observed in the presence of S-CMC-Lys or 8-bromoadenosine-3',5'-cyclic monophosphate was also confirmed by HPLC assay of GSH on a confluent monolayer of respiratory cells. Western blot analysis confirmed the presence of CFTR in WI-26VA4 cells. This study suggests that S-CMC-Lys is able to stimulate a channel-mediated GSH secretion by human respiratory cells: electrophysiological and pharmacological characteristics of this channel are similar to those of the CFTR channel.

S-carbocysteine-lysine salt monohydrate and cAMP cause non-additive activation of the cystic fibrosis transmembrane regulator channel in human respiratory epithelium.

S-Carbocysteine-lysine salt monohydrate (S-CMC-Lys) has been shown to open a Cl- channel in the trachea, thus aiding fluid secretion. The aim of this study was to characterize the channel and the action mechanism on a culture line of human respiratory epithelial cells. The patch-clamp technique (in cell-attached or inside-out configuration) and conventional micro-electrodes were used. The activity and density of a cAMP-dependent Cl- channel, identical to the cystic fibrosis transmembrane regulator (CFTR) channel, proved to be maximally stimulated by 100 microM S-CMC-Lys present in the cAMP-free cell incubation medium for 240-290 min (cell-attached configuration). Subsequent addition of cAMP to the medium did not determine any further activation. S-CMC-Lys acted mostly indirectly as, when placed in direct contact with a membrane patch, activation of the CFTR channel was nil (cytoplasmic side) or limited (external side).

Effects of levodropropizine on vagal afferent C-fibres in the cat.

1. Levodropropizine (LVDP) is an effective antitussive drug. Its effects on single-unit discharge of vagal afferent C-fibres were tested in anaesthetized cats to assess whether an inhibition of vagal C-fibres is involved in its antitussive properties. Vagal C-fibres, identified by their response to phenylbiguanide (PBG), were recorded via suction electrodes from the distal part of the cut vagus. Based on their response to lung inflation, C-fibres were classified as pulmonary (19 fibres) or non-pulmonary (6 fibres). 2. PBG increased the discharge rate of both C-fibre types and activated a respiratory reflex causing apnoea. This reflex was abolished when the second vagus nerve was cut as well, while PBG-mediated stimulation of the C-fibres was not affected by vagotomy. 3. LVDP was administered intravenously and the C-fibre response to PBG was compared with that before administration of the drug. LVDP reduced both the duration of apnoea and the response of the C-fibre to PBG. 4. Comparison of the C-fibre responses to PBG and to a mixture of PBG and LVDP revealed that the period of apnoea was shortened and the discharge rate of the C-fibre reduced when LVDP was present. 5. The LVDP-induced inhibition of the C-fibre response to PBG was on average 50% in pulmonary and 25% in non-pulmonary fibres. 6. These results suggest that LVDP significantly reduces the response of vagal C-fibres to chemical stimuli. It is, thus, likely that the antitussive effect of LVDP is mediated through its inhibitory action on C-fibres.

Pharmacological modulation of bronchial anaphylaxis induced by aerosol challenge in anaesthetized guinea-pigs.

Anaphylactic bronchoconstriction provoked by aerosol challenge, and its pharmacological modulation, has been investigated in anaesthetized pump-ventilated guinea-pigs actively sensitized to ovalbumin (OA). Aerosol challenge (OA 0.03-10 mg ml-1) provoked immediate bronchoconstriction, the degree of which, and its rate of development, was directly related to antigen concentration. Concomitant changes in heart rate and systemic arterial blood pressure following aerosol challenge were reduced compared with systemic (OA, 1 mg kg-1 i.v.) challenge. Unlike systemic challenge, aerosol challenge did not cause a concomitant fall in either circulating leukocyte or platelet count. When a submaximal (microshock) aerosol challenge stimulus (OA, 0.3 mg ml-1, 5 s) was employed, bronchoconstriction was markedly reduced by mepyramine (2 mg kg-1 i.v.). The residual component of bronchoconstriction was enhanced by indomethacin (10 mg kg-1 i.v.), an effect which was reversed by either BW755C (30 mg kg-1 i.v.) or FPL55712 (10 mg kg-1 i.v.). When a supramaximal (macroshock) aerosol challenge stimulus (OA, 10 mg ml-1, 5 s) was employed, bronchoconstriction was also markedly reduced by mepyramine. Residual bronchoconstriction was not altered by indomethacin, slowed but not reduced by indomethacin plus BW755C, and substantially reduced by indomethacin plus FPL55712. The successive incremental antagonism of anaphylactic bronchoconstriction by mepyramine and mepyramine plus indomethacin and FPL55712 indicates that the predominant mediators involved are histamine and leukotrienes, respectively. The failure of indomethacin plus BW755C to inhibit the mepyramine-resistant bronchoconstriction provoked by OA macroshock may reflect the increased generation of leukotrienes via a 5-lipoxygenase isoenzyme resistant to inhibition by BW755C. 7. Aerosol challenge of actively sensitized anaesthetized guinea-pigs by this method may be a useful model of human allergic bronchoconstriction, particularly when the effects of a drug given itself as an aerosol are being evaluated.

Immediate anaphylactic bronchoconstriction induces airway hyperreactivity in anaesthetized guinea-pigs.

1. The possible acute occurrence of airway hyperreactivity after immediate-type bronchial anaphylaxis has been investigated in anaesthetized guinea-pigs actively sensitized to ovalbumin (OA). 2. Aerosol challenge (OA 10 mg ml-1, 5 s) provoked immediate bronchoconstriction which was substantially, although incompletely, reversed by isoprenaline (Iso) infusion (1 microgram kg-1 min-1) for 10 min). 3. Bronchoconstrictor responses to 5-hydroxytryptamine (5-HT) were enhanced in challenged animals when compared to those in non-challenged animals that had also received Iso. This was seen as a leftward shift in the location of the dose-response curve for the bronchoconstrictor effect of 5-HT (dose-ratio 2.45, 95% confidence limits 1.77-3.38; P less than 0.01). This phenomenon was associated with pulmonary infiltration of polymorphonuclear leukocytes, which was not modified by Iso treatment. 4. Iso infusion alone caused a slight enhancement of airway reactivity seen as a small leftward shift of the dose-response curve for the bronchoconstrictor effect of 5-HT (dose-ratio 1.51, 95% confidence limits 1.07-2.13; P less than 0.05). 5. These results support a causal relationship between acute pulmonary inflammation and airway hyperreactivity in an animal model of human allergic asthma.

Adrenaline-induced tracheal relaxation ex vivo is depressed following aerosol antigen challenge of sensitized guinea-pigs.

We investigated the changes in beta-adrenoceptor responses induced in guinea-pig tracheal and cardiac tissues by the anaphylactic reaction. Antigen aerosol challenge in sensitized guinea-pigs resulted in a marked reduction in adrenaline relaxation in isolated trachea ex vivo. The isoprenaline effect was also slightly decreased by antigen exposure, suggesting a possible impairment of tracheal beta-adrenoceptor function. On the other hand, the chronotropic and inotropic activity of adrenaline in isolated atria was not modified by the anaphylactic shock, suggesting a specific involvement of lung beta-adrenoceptors in the allergic reaction.

Bradykinin and substance P potentiate acetylcholine-induced bronchospasm in guinea-pig.

The interaction of threshold doses of bradykinin (BK) and substance P (SP) with acetylcholine (ACh)-induced bronchospasm was investigated in anaesthetized guinea-pigs. The two peptides potentiated the ACh-induced bronchospasm, an effect which did not seem to depend on prostaglandin release. On the other hand, vagotomy abolished the capacity of BK and SP to potentiate the ACh-induced bronchospasm. The present data suggest a possible involvement of BK and SP in the genesis of airway hyperreactivity.

Effect of 3'-hydroxyfarrerol on airway hyperreactivity induced by acute cigarette smoke exposure in guinea pigs.

The (+/-)-3'-hydroxyfarrerol (IdB 1031) is a new drug endowed with an interesting mucokinetic activity. In this study the effectiveness of IdB 1031 has been verified in a model of airway hyperreactivity and lung inflammation induced in anaesthetized guinea pig by active cigarette smoke exposure. IdB 1031 (500 mg/kg per os) completely inhibited the capacity of cigarette smoke to induce airway hyperreactivity. IdB 1031 also inhibited the recruitment of proinflammatory cells within the airway lumen as showed in bronchoalveolar lavage fluids. In line with these experiments IdB 1031 inhibited 5-lipoxygenase with an IC50 of 7.36 x 10(-6) M in human leukocytes challenged by A-23187 (2 microM). A significant reduction of the above parameters was observed also in animals exposed to smoke after repeated treatment with IdB 1031 at 200 mg/kg per os for 15 days. These results show that IdB 1031 is a promising drug with a favourable spectrum of activities on the respiratory tract.

Effectiveness of levodropropizine against cigarette smoke-induced airway hyperreactivity: possible mechanism.

We verified the possible effect of the new antitussive drug levodropropizine on airway hyperreactivity and lung inflammation induced by cigarette smoke exposure in anaesthetized guinea-pigs. Levodropropizine, administered by aerosol at 25 mg/ml for 30 s completely prevented smoke induced airway hyperreactivity. The protective effect was early in onset (3 min) and lasted up to 30 min. The same dose of codeine, administered in the form of an aerosol, decreased the increase in airway responsiveness induced by smoke inhalation slightly but not significantly. In parallel with the functional results, levodropropizine also inhibited the recruitment of inflammatory cells triggered by smoke exposure within the airway lumen. When levodropropizine was administered i.v. to anaesthetized guinea-pigs, it reduced the bronchocontractile effect of capsaicin dose-dependently, whereas it was without effect against substance P-induced bronchoconstriction. These data demonstrate the ability of levodropropizine to counteract the hyperreactive phenomenon and the associated inflammatory event induced by cigarette smoke exposure, an effect which might depend on its capacity to modulate the activation of the peptidergic system.

Airway hyperreactivity follows anaphylactic microshock in anaesthetized guinea-pigs.

Actively sensitized guinea-pigs were challenged with a dose of ovalbumin aerosol (300 micrograms ml-1, 5 s) that caused submaximal bronchoconstriction (anaphylactic microshock). Airway reactivity to i.v. 5-hydroxytryptamine (5-HT), i.v. acetylcholine (ACh) and aerosolised 5-HT was assessed subsequently. In addition, histological studies were carried out to investigate possible pulmonary recruitment of inflammatory cells following anaphylactic microshock. Following antigen challenge, there was a significant (P less than 0.05) increase in airway reactivity. This phenomenon was temporally separated (60-120 min) from the initial anaphylactic bronchoconstriction, but occurred in the absence of detectable lung pathology other than minor epithelial necrosis. Whilst histamine aerosol (100 micrograms ml-1, 5 s) did not induce airway hyperreactivity, pretreatment with the histamine H1 receptor antagonist mepyramine (2 mg kg-1 i.v.) prevented that occurring following antigen challenge. These observations suggest that in the pathogenesis of airway hyperreactivity, mediator release from resident leukocytes is initially more important than pulmonary infiltration of circulating cells. Depletion of a putative epithelium-derived relaxant factor may also play a contributory role. The anaphylactic release of histamine may modulate the release of secondary mediators of airway hyperreactivity.

Defibrotide, an antithrombotic substance which prevents myocardial contracture in ischemic rabbit heart.

Defibrotide, a polydeoxyribonucleotide obtained from mammalian lungs, reduced in a dose-dependent fashion the ischemic contracture due to low perfusion (0.2 ml/min) of isovolumic left heart of rabbit and abolished the irregular rhythm of the heart, thereby restoring the cardiomechanical activity upon reperfusion (20 ml/min). Defibrotide stimulated the release of PG-like material from the heart in a dose-dependent manner without modifying the basal contractility. Both PGE2 and PGI2 (10 ng/ml) have an antiischemic activity on this preparation as shown by the partial reduction of the ischemic contracture and by the improvement of heart contractility upon reperfusion. Indomethacin infusion (1 microgram/ml) completely removed both the antiischemic activity of Defibrotide (400 micrograms/ml) and its ability to increase the generation of prostaglandins in the rabbit heart. These results suggest that Defibrotide has a beneficial influence on ischemic rabbit heart through an increase in prostaglandin synthesis. However other mechanisms not necessarily related to prostaglandin generation, such as a direct effect on membrane function deactivation and mitochondrial Ca2+ overload, should be considered in explaining the antiischemic activity of Defibrotide in the rabbit heart.

Levodropropizine reduces capsaicin- and substance P-induced plasma extravasation in the rat trachea.

We investigated the effect of the non-opioid, peripherally acting antitussive agent levodropropizine to reduce neurogenic plasma extravasation in the rat trachea. Levodropropizine (10, 50 and 200 mg/kg) reduced in a dose-dependent manner the extravasation of Evans blue dye evoked by capsaicin. Levodropropizine inhibited also substance P-evoked extravasation, whereas it did not affect the extravasation evoked by platelet activating factor. Levodropropizine (10 and 100 microM) did not affect the contraction produced by [Sar9,Met(O2)11]substance P, a selective agonist for tachykinin NK1 receptors, in the rat urinary bladder in vitro. These data indicate that levodropropizine inhibits capsaicin-induced plasma extravasation: (a) acting at a postjunctional level; (b) exhibiting neuropeptide selectivity and; (c) via a mechanism independent of tachykinin NK1 receptor blockade. Irrespective of the mechanism, this novel antiinflammatory action of levodropropizine underlines its potential role in inflammatory airway diseases such as bronchial asthma.

Involvement of arachidonic acid metabolites in beta-adrenoceptor desensitization: functional and biochemical studies.

The prolonged in vitro perfusion of rat lung with isoproterenol (Iso) induced a desensitization of beta-adrenoceptors which was dose- and time-dependent. The decrease in functional responsiveness of rat lung parenchyma to the beta-agonist correlated well with the loss of [3H]dihydroalprenolol ([3H]DHA) binding sites and adenylate cyclase activity after the beta-adrenoceptor desensitization procedure. The cyclooxygenase inhibitor indomethacin prevented the beta-adrenoceptor desensitization as was shown by the restored isoproterenol-induced relaxation in rat lung parenchyma strips and adenylate cyclase activity after the milder desensitization procedure. Inhibition of the arachidonic acid cascade at different levels with different compounds such as BW 755C and betamethasone prevented the desensitization of beta-adrenoceptors. These findings suggest a role for arachidonic acid metabolites in beta-adrenoceptor desensitization. The possible sites of action of arachidonic acid metabolites are also discussed in relation to the inability of indomethacin to prevent the desensitization of beta-adrenoceptors that was induced by the higher Iso concentration used.

Beta-adrenoceptor desensitization induced by antigen challenge in guinea-pig trachea.

As beta-adrenoceptor function in the lung could be relevant in asthma, we carried out a functional and biochemical study of the possible occurrence of beta-receptor desensitization after the anaphylactic reaction induced in vitro in actively sensitized guinea-pig tracheas. The relaxing effect of epinephrine and vasoactive intestinal polypeptide (VIP) was tested in tracheal strips. Binding was studied with tracheal membranes and 125I-cyanopindolol. Antigen challenge resulted in a marked decrease of epinephrine-induced relaxation paralleled by a 50% reduction in beta-receptor number. The adrenergic system was specifically affected since VIP-induced relaxation was not modified by the anaphylactic reaction. In some experiments tissues were pretreated with hydrocortisone or indomethacin. Both these drugs prevented antigen exposure from impairing epinephrine relaxation, suggesting the involvement of eicosanoids in this phenomenon. Our data clearly indicate the occurrence of beta-receptor desensitization as a consequence of the anaphylactic reaction, thus impairment of the adrenergic system might play a role in asthma.

Antioxidant activity of carbocysteine lysine salt monohydrate.

BACKGROUND: Reactive oxygen radicals are involved in many respiratory diseases, including chronic obstructive pulmonary disease (COPD). Carbocysteine lysine salt monohydrate (CLS) is a mucoactive drug effective in the treatment of bronchopulmonary diseases characterized by mucus alterations, including COPD. In the present study, the antioxidant activity of CLS was studied in vitro in three different oxygen radical producing systems, i.e. bronchoalveolar lavages (BAL) from patients affected by COPD, ultrasound treated human serum and cultured human lung endothelial cells challenged with elastase. METHODS: BAL, exposed or not to different concentrations of CLS (1.5-30 mM), was assayed for free radical content by fluorometric analysis of DNA unwinding (FADU) or by cytochrome c reduction kinetics. Human serum was treated with ultrasound in the presence or absence of CLS (1.5, 2.5 mM) or N-acetyl cysteine (NAC; 4, 5 mM) and assayed for free radical content by FADU. Human endothelial cells cultured in vitro from pulmonary artery were incubated with elastase (0.3 IU/mL), in the presence or absence of glutathione (GSH; 0.65 mM) or CLS (0.16 mM). The supernatant was tested for cytochrome c reduction kinetics whereas cell homogenates were assessed for xanthine oxidase (XO) content by SDS-PAGE. RESULTS: Results showed that CLS is more effective as an in vitro scavenger in comparison to GSH and NAC. CLS reduced the damage of DNA from healthy donors exposed to COPD-BAL and was able to quench clastogenic activity induced in human serum by exposure to ultrasound at concentrations as low as 2.5 mM. NAC protect DNA from radical damage, starting from 5 mM. In human lung endothelial cells cultured in presence of elastase, CLS (0.16 mM) decreased xanthine oxidase activity. CONCLUSIONS: These results suggest that CLS could act by interfering with the conversion of xanthine dehydrogenase into superoxide-producing xanthine oxidase. The antioxidant activity of CLS could contribute to its therapeutic activity by reducing radical damage to different lung structures.

Efficacy and tolerability of levodropropizine in adult patients with non-productive cough. Comparison with dextromethorphan.

The results of a double-blind, randomized clinical trial involving 209 adult patients of either sex with moderate non-productive cough are reported. The therapeutic efficacy and the tolerability of levodropropizine syrup (60 mg t.i.d. for 5 days) was evaluated in comparison with dextromethorphan syrup (15 mg t.i.d. for 5 days). Efficacy was assessed by the number of coughing spells in a 6h period, the cough frequency classes, the cough intensity and the night awakenings due to cough. Tolerability was evaluated by laboratory results, vital signs and any adverse event occurred during the clinical trial, including presence or absence of somnolence. Independently from the underlying pathology and from the degree of baseline cough severity, the number of coughing spells was significantly (P < 0.05) reduced by both levodropropizine and dextromethorphan already after the 2nd day of treatment, the effect and its time of onset being similar for both drugs. Cough intensity was significantly (P < 0.01) reduced by both drugs throughout the treatment, at an earlier time with levodropropizine than with dextromethorphan. Concurrently with the relief of cough, the number of night awakenings was decreased remarkably and significantly (P < 0.05), with levodropropizine displaying an improvement significantly higher (P < 0.05) than dextromethorphan. No change in laboratory tests values was considered clinically relevant and vital signs were not clinically affected by the study drugs. The number of patients reporting adverse events was significantly higher (P < 0.05) in the dextromethorphan (12.1%) than in the levodropropizine (3.6%) group. Overall, somnolence was reported for a low percentage of patients with both drugs, with the percentage of patients experiencing this side effect being one half in the group treated with levodropropizine (4.6%) as compared with dextromethorphan (10.4%). These results confirm the antitussive effectiveness of levodropropizine and point out a more favourable benefit/risk profile when compared to dextromethorphan.

Protective effect of ketoprofen lysine salt on interleukin-1beta and bradykinin induced inflammatory changes in hamster cheek pouch microcirculation.

OBJECTIVE: The purpose of this study was to assess the efficacy of topically applied ketoprofen lysine salt (KLS), a cyclooxygenase inhibitor, against the inflammatory changes induced by interleukin-1beta (IL-1beta) and bradykinin (BK) in hamster cheek pouch microcirculation. In addition, we characterised the pharmacological regulation of IL-1beta activity in this model. MATERIALS AND METHODS: Male Syrian hamsters were used. Microcirculation was visualised by fluorescent microscopy. Leukocyte adhesion, permeability, perfused capillary length (PCL) and capillary red blood cell (RBC) velocity were evaluated. TREATMENTS: KLS (25 microg/ml/min to 1.6 mg/ml/min) was topically applied for 3 min before topically administered IL-1beta (1microg/ml) and BK (10(-4) M). Monoclonal anti-mouse IL-1beta receptor antagonist (200 ng/ml), BK-B2 receptor antagonist (10(-6) M), PAF inhibitor (10(-5) M) and cycloheximide (10 microg/ml) were added topically 15, 10, 15 and 60 min, respectively, before IL-1beta (1 microg/ml). RESULTS: IL-1beta caused a significant increase in microvascular permeability, a decrease in capillary RBC velocity followed by increased leukocyte adhesion in postcapillary venules. BK caused a marked increase in leukocyte adhesion and no decrease in PCL and RBC velocity. Treatment with KLS significantly inhibited both the leukocyte adhesion and microvascular leakage induced by the two mediators. The inflammatory effects induced by IL-1beta were reduced by blockade of IL-1beta receptors and by a BK-B2 receptor antagonist but were not affected by a PAF antagonist and protein synthesis inhibition. CONCLUSIONS: These results demonstrate that KLS is effective in preventing early inflammatory changes induced by both IL-1beta and BK in the capillary network. Prostaglandin release and BK are essential components for IL-beta mediated responses, whereas neither PAF nor new protein synthesis appear to be linked to the early inflammatory changes induced by IL-1beta.

Interleukin-1 beta: a possible mediator of lung inflammation and airway hyperreactivity.

Interleukin-1 (IL-1), a peptide released from monocytes/macrophages, plays an important role in the inflammatory and immune responses. Airway hyperreactivity and the underlying airway inflammation are common features in asthma pathology. We investigated and characterized the inflammatory alterations induced within the guinea-pig respiratory system by IL-1 beta. Injection of IL-1 beta (1-6 micrograms/animal) into the pleural space resulted in a dose-dependent inflammatory response, as shown by the formation of pleural exudate and leucocyte recruitment. A threshold dose of IL-1 beta (1 micrograms/animal) markedly potentiated the inflammatory reaction triggered by the classical proinflammatory agent croton oil, underlining the amplifying role of IL-1 beta in the inflammatory events. The inflammatory process induced by intrapleural injection of IL-1 beta (6 micrograms/animal) was associated with the development of a hyperreactive phenomenon which involved both the peripheral and large airways. In fact, increased contractile activity of histamine was evident in the tracheas and parenchymal strips isolated from guinea-pigs exposed to IL-1 beta. These results provide evidence for a possible role of IL-1 beta in the genesis of airway inflammation and bronchial hyperreactivity.

Nedocromil sodium prevents airway hyperreactivity induced by cigarette smoke in anaesthetized guinea-pigs.

Increased airway reactivity and influx of inflammatory cells into the airways have been demonstrated both in smokers and after smoke exposure in animal studies. We investigated the ability of nedocromil sodium and hydrocortisone to protect from the pathological alterations induced by direct cigarette smoke exposure in anaesthetized guinea-pigs. Active inhalation of cigarette smoke (15 s/min for 10 min) induced airway hyperreactivity, as shown by the enhanced bronchoconstrictor effect of histamine and was associated with an increase in total cells, macrophages and eosinophils in the BAL fluid. Nedocromil sodium given by aerosol (3 and 10 mg/ml for 30 s) completely prevented the ability of cigarette smoke to potentiate histamine induced bronchoconstriction. In parallel, nedocromil sodium inhibited the development of the inflammatory reaction triggered by smoke exposure. Hydrocortisone pretreatment (50 mg/kg s.c. twice) did not abolish the smoke induced airway hyperreactivity, nor did it inhibit the recruitment of proinflammatory cells within the airway lumen. Sensory neuropeptides have been demonstrated to be involved in the development of smoke induced airway hyperreactivity. The efficacy of nedocromil sodium in this model might depend on its ability to modulate the activation of the peptidergic system.