Secondary bronchiolitis obliterans organising pneumonia in a patient with carbamazepine-induced hypogammaglobulinaemia.

Here we describe a case of a secondary bronchiolitis obliterans organizing pneumonia (BOOP), which was associated with repeated respiratory infections caused by carbamazepine (CBZ)- induced hypogammaglobulinaemia. A 49-year-old woman had been treated with CBZ (400 mg/day). Two and a half years later, she developed of dyspnea with productive cough and high-grade fever. Chest roentgenogram and computed tomography showed bilateral infiltrates in lower lung fields. Her laboratory findings revealed severe hypogammaglobulinaemia, suggesting that an immune system disorder caused pulmonary infection. Histological examination by trans-bronchial lung biopsy (TBLB) demonstrated that many foamed alveolar macrophages were obstructing the alveolar ducts and adjacent alveoli, suggesting BOOP. After cessation of CBZ, the hypogammaglobulinaemia and chest roentgenogram findings markedly improved. The present case suggests that CBZ may have some adverse effects on the immune system and cause frequent airway infections, and that secondary BOOP could be induced by repeated infections caused by CBZ-induced hypogammaglobulinaemia.

Prolonged eosinophil production after allergen exposure in IFN-gammaR KO mice is IL-5 dependent.

Asthma is a T helper 2 (Th2)-driven inflammatory process characterized by eosinophilia. Prolonged airway eosinophilia is commonly observed in asthma exacerbations. Our aim was to evaluate whether eosinophilia in prolonged allergic inflammation is associated with a continuous supply of new eosinophils to the airways, and how this is regulated. Ovalbumin (OVA)-sensitized interferon-gamma receptor knockout mice (IFN-gammaR KO), known to maintain a long-lasting eosinophilia after allergen exposure, were compared to wild type (wt) controls. Animals were exposed to OVA or phosphate-buffered saline on three consecutive days, and bone marrow (BM), blood and bronchoalveolar lavage (BAL) samples were collected 24 h, 7 and 21 days later. Newly produced cells were labelled using bromodeoxyuridine (BrdU). Serum IL-5 was measured and its role was investigated by administration of a neutralizing anti-IL-5 antibody. In-vitro eosinophilopoiesis was examined in both groups by a colony-forming assay. Allergen challenge increased eosinophils in BM, blood and BAL, in both IFN-gammaR KO and wt mice, both 24 h and 7 days after the last allergen exposure. At 21 days after the last exposure, only IFN-gammaR KO mice maintained significantly increased eosinophil numbers. Approximately 50% of BAL granulocytes in IFN-gammaR KO were produced during the last 6 days. Interleukin (IL)-5 concentration was increased in IFN-gammaR KO mice, and anti-IL-5 reduced eosinophil numbers in all compartments. Increased numbers of eosinophil colonies were observed in IFN-gammaR KO mice after allergen exposure versus controls. In this model of a Th2-driven prolonged allergic eosinophilia, new eosinophils contribute to the extended inflammation in the airways by enhanced BM eosinophilopoiesis in an IL-5-dependent manner.

Allergen stimulates bone marrow CD34(+) cells to release IL-5 in vitro; a mechanism involved in eosinophilic inflammation?

The specific mechanisms that alter bone marrow (BM) eosinophilopoiesis in allergen-induced inflammation are poorly understood. The aims of this study were to evaluate (a) whether the number of BM CD34(+) cells is altered due to allergen sensitization and exposure in vivo and (b) whether BM CD34(+) cells produce and release interleukin (IL)-5, IL-3 and granulocyte macrophage-colony stimulating factor (GM-CSF) after stimulation in vitro. A mouse model of ovalbumin (OVA)-induced airway inflammation was used. Bone marrow CD34(+) cells were cultured in vitro and the cytokine release was measured by enzyme-linked immunosorbent assay. The IL-5-production from CD34(+) cells was confirmed by immunocytochemistry. Airway allergen exposure increased the number of BM CD34(+) cells (P = 0.01). Bone marrow CD34(+) cells produced IL-5 when stimulated with the allergen OVA in vitro, but not IL-3 or GM-CSF. Nonspecific stimulus with calcium ionophore and phorbol-myristate-acetate of BM CD34(+) cells caused release of IL-5, IL-3 and GM-CSF. The induced release of IL-5 was increased in alum-injected vs naive mice (P = 0.02), but was not affected by allergen sensitization and exposure. The release of IL-3 and GM-CSF was increased after allergen sensitization and exposure (P < 0.02). In conclusion, allergen can stimulate BM CD34(+) cells to produce IL-5 protein. It is likely that the CD34(+) cells have autocrine functions and thereby regulate the early stages of BM eosinophilopoiesis induced by airway allergen exposure. Alum, a commonly used adjuvant, enhances the release of IL-5 and may thereby enhance eosinophilopoiesis.

Beta-adrenoceptor stimulation and neutrophil accumulation in mouse airways.

This study characterised the effect of beta-adrenoceptor stimulation on endotoxin-induced accumulation of neutrophilic granulocytes in mouse airways, where the cytokines interleukin (IL)-6 and macrophage inflammatory protein (MIP)-2 are involed as mediators. The beta2-adrenoceptor agonist salbutamol (0.025-250 fMol) was administered intranasally in mice 24 h prior to administration of endotoxin (10 microg) intranasally. Bronchoalveolar lavage (BAL) fluid and venous blood, respectively, was harvested (6 or 24 h) after administration of endotoxin. Salbutamol substantially decreased the number of neutrophils in BAL fluid from endotoxin-exposed (6 and 24 h) mice and this effect was dose dependent (24 h). Pretreatment with the beta-adrenoceptor antagonist propranolol attenuated the inhibitory effect of salbutamol on BAL neutrophils (6 and 24 h), an attenuation that was not due to any unspecific effect of propranolol. Salbutamol also substantially decreased IL-6, but not MIP-2 in BAL fluid (6 h). In contrast to BAL fluid, salbutamol caused a moderate increase in blood neutrophils (24 h). In conclusion, as indicated in mouse airways in vivo, beta-adrenoceptor stimulation prior to endotoxin exposure inhibits the induced accumulation of neutrophils at a time point much later than that anticipated from its bronchodilatory effect. Even though the detailed molecular mechanisms behind this sustained "anti-inflammatory" effect remain unknown, it seems likely that this effect is in part due to a decrease in the local concentration of interleukin-6.

Xanthine oxidase inhibition reduces reactive nitrogen species production in COPD airways.

Reactive nitrogen species (RNS) have been reported to be involved in the inflammatory process in chronic obstructive pulmonary disease (COPD). However, there are no studies on the modulation of RNS in COPD. It was hypothesised that inhibition of xanthine oxidase (XO) might decrease RNS production in COPD airways through the suppression of superoxide anion production. Ten COPD and six healthy subjects participated in the study. The XO inhibitor allopurinol (300 mg x day(-1) p.o. for 4 weeks) was administered to COPD patients. RNS production in the airway was assessed by 3-nitrotyrosine immunoreactivity and enzymic activity of XO in induced sputum as well as by exhaled nitric oxide (eNO) concentration. XO activity in the airway was significantly elevated in COPD compared with healthy subjects. Allopurinol administration to COPD subjects significantly decreased XO activity and nitrotyrosine formation. In contrast, eNO concentration was significantly increased by allopurinol administration. These results suggest that oral administration of the xanthine oxidase inhibitor allopurinol reduces airway reactive nitrogen species production in chronic obstructive pulmonary disease subjects. This intervention may be useful in the future management of chronic obstructive pulmonary disease.

iNOS depletion completely diminishes reactive nitrogen-species formation after an allergic response.

Nitric oxide (NO) shows proinflammatory actions mainly via reactive nitrogen species (RNS) formation through superoxide- and peroxidase-dependent mechanisms. The purpose of this study was to examine the role of inducible NO synthase (iNOS) in RNS production, airway hyperresponsiveness, and inflammation after allergen challenge. Ovalbumin (OVA)-sensitised, iNOS-deficient and wild-type mice were used. RNS production was assessed by nitrotyrosine (NT) immunoreactivity in the airways. Airway inflammation and responsiveness were evaluated by eosinophil accumulation and methacholine (i.v.) challenge, respectively. In wild-type mice, OVA-inhalation challenge increased iNOS immunoreactivity in airway epithelial cells as well as iNOS protein measured by Western blotting. The total amounts of nitrite and nitrate in bronchoalveolar lavage (BAL) fluid were increased, and NT immunoreactivity was also observed abundantly in airway inflammatory cells. In iNOS-deficient mice, both iNOS expression and NT formation were completely abolished, and the total amounts of nitrite and nitrate in BAL fluid were significantly decreased. In contrast, OVA-induced airway eosinophil recruitment and hyperresponsiveness were observed almost equally in wild-type and iNOS-deficient mice. These data suggest that reactive nitrogen species production after allergic reaction occurs totally via inducible nitric oxide synthase-dependent pathways. Allergen-mediated airway eosinophil recruitment and hyperresponsiveness appear to be independent of reactive nitrogen species production.

[Measurement of airway hyperresponsiveness].

Airway hyperresponsiveness (AHR) refers to an abnormal increase in airway responses, such as airflow limitation, to nonselective stimuli that are divided into direct (acting directly on the effector organs) and indirect (mediated via inflammatory or neuronal cells). The mechanisms of AHR in asthma have received much attention but remain uncertain. Well-standardized methods for measuring AHR represent important tools for the diagnosis and monitoring of asthma. The measurement of AHR is generally based on the dose-response curve that is obtained after exposure to a stimulus (usually inhalation of increasing doses of aerosolized mediator) followed by the assessment of lung function. Indirect challenges, as well as direct challenges, may provide useful information on the multiple pathways leading to AHR, towards improvements in the management of asthma.

Eosinophilopoiesis in a murine model of allergic airway eosinophilia: involvement of bone marrow IL-5 and IL-5 receptor alpha.

The airway inflammation in asthma is dominated by eosinophils. The aim of this study was to elucidate the contribution of newly produced eosinophils in airway allergic inflammation and to determine mechanisms of any enhanced eosinophilopoiesis. OVA-sensitized BALB/c mice were repeatedly exposed to allergen via airway route. Newly produced cells were identified using a thymidine analog, 5-bromo-2'-deoxyuridine, which is incorporated into DNA during mitosis. Identification of IL-5-producing cells in the bone marrow was performed using FACS. Bone marrow CD3+ cells were enriched to evaluate IL-5-protein release in vitro. Anti-IL-5-treatment (TRFK-5) was given either systemically or directly to the airways. IL-5R-bearing cells were localized by immunocytochemistry. Repeated airway allergen exposure caused prominent airway eosinophilia after three to five exposures, and increased the number of immature eosinophils in the bone marrow. Up to 78% of bronchoalveolar lavage (BAL) granulocytes were 5-bromo-2'-deoxyuridine positive. After three allergen exposures, both CD3+ and non-CD3 cells acquired from the bone marrow expressed and released IL-5-protein. Anti-IL-5 given i.p. inhibited both bone marrow and airway eosinophilia. Intranasal administration of anti-IL-5 also reduced BAL eosinophilia, partly via local effects in the airways. Bone marrow cells, but not BAL eosinophils, displayed stainable amounts of the IL-5R alpha-chain. We conclude that the bone marrow is activated by airway allergen exposure, and that newly produced eosinophils contribute to a substantial degree to the airway eosinophilia induced by allergen. Airway allergen exposure increases the number of cells expressing IL-5-protein in the bone marrow. The bone marrow, as well as the lung, are possible targets for anti-IL-5-treatment.

Induction of nitric oxide synthase by lipopolysaccharide inhalation enhances substance P-induced microvascular leakage in guinea-pigs.

Inducible nitric oxide (NO) synthase (iNOS)-mediated hyperproduction of NO in airways has been reported in asthmatic patients. However, the role of NO in the pathogenesis of asthma has not yet been fully elucidated. The aim of this study was to examine whether the iNOS-derived NO affects airway microvascular leakage, one of the characteristic features of asthmatic airway inflammation. Guinea-pigs were exposed to lipopolysaccharide (LPS) (1 mg x mL(-1)) by inhalation in order to induce iNOS in the airways, and the histochemical staining of reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-diaphorase activity was determined 5 h after the inhalation to confirm the iNOS induction. Airway microvascular leakage to subthreshold doses of substance P (0.3 microg x kg(-1), i.v.) was also examined in the absence and presence of an iNOS inhibitor (aminoguanidine) in LPS- or saline-exposed (control) animals using Evans blue dye and Monastral blue dye. In the LPS-exposed animals, increased NADPH-diaphorase activity was observed in the airway microvasculature compared with the control animals. Substance P caused significant airway microvascular leakage assessed by Evans blue dye in all airway levels in the LPS-exposed animals but not in the control group. This was also confirmed by Monastral blue dye extravasation. Aminoguanidine abolished this LPS-induced enhancement of plasma leakage to substance P without changing the systemic blood pressure. These results may suggest that inducible nitric oxide synthase-derived nitric oxide is capable of potentiating neurogenic plasma leakage in airways.

Impairment of neural nitric oxide-mediated relaxation after antigen exposure in guinea pig airways in vitro.

Nitric oxide (NO), a neurotransmitter of inhibitory nonadrenergic noncholinergic (iNANC) nerves in airways, is a radical with a short half-life, and its function may be modified by airway inflammation. To test this hypothesis, we examined whether airway allergic inflammation affects iNANC responses mediated by NO in guinea pigs in vitro. Animals sensitized with ovalbumin (OA) were challenged with 0.03% OA (OA group) or saline (saline group) by inhalation on 3 consecutive days. On the day after the final challenge, iNANC responses elicited by electrical field stimulation (2 to 16 Hz) or relaxation responses to 3-morpholinosydnonimine (SIN-1), 10(-8) to 10(-4) M, were obtained in the tracheal strips precontracted by histamine (3 x 10(-6) M) in the presence of atropine and propranolol (both 10(-6) M). The INANC responses of the OA group were significantly attenuated compared with those of the saline group (p < 0.05), and the inhibitory effect of a NO synthase (NOS) inhibitor, Nm-nitro-L-arginine methyl ester, on the INANC responses was abolished in the OA group. SIN-1-induced tracheal smooth muscle relaxation was also significantly affected by antigen exposure (p < 0.05), the effect of which disappeared in the presence of a NO scavenger, carboxy PTIO (3 x 10(-6) M). The impairment of the INANC responses after antigen exposure was significantly restored by superoxide dismutase (1,000 U/ml), especially at lower frequencies. Histochemical demonstration of NADPH-diaphorase-positive nerves representing neural NOS density was not different between the two groups. These results suggest that allergic airway inflammation impairs neural NO-induced relaxation, presumably by inhibiting the access of neural NO to the airway smooth muscle.

Role of endogenous nitric oxide in airway microvascular leakage induced by inflammatory mediators.

This study examines the role of endogenous nitric oxide (NO) in airway microvascular leakage induced inflammatory mediators, which play an important role in asthmatic airways. Guinea-pigs were anesthetized and mechanically-ventilated with monitoring of arterial blood pressure, and airway microvascular leakage induced by intravenous injection of substance P (SP), leukotriene D4 (LTD4) and histamine was evaluated using Evans blue dye and Monastral blue dye in the presence and absence of the NO synthase inhibitors, L-NG-nitroarginine methyl ester (L-NAME) and L-NG-monomethyl arginine (L-NMMA). The effect of a soluble guanylate cyclase inhibitor, LY83583, on SP-induced dye leakage was also examined. Intravenous injection of SP (1 microgram.kg-1), LTD4 (1 microgram.kg-1) and histamine (100 micrograms.kg-1) significantly increased dye extravasation at all airway levels. Pretreatment with L-NAME (10 mg.kg-1 i.v.) and L-NMMA (100 mg.kg-1 i.v.) significantly inhibited SP-induced extravasation, and L-arginine (100 mg.kg-1 i.v.) reversed L-NAME-induced inhibition. L-NAME (10 mg.kg-1 i.v.) also significantly inhibited LTD4-induced dye extravasation only in central airways, and this inhibitory effect was abolished by a neurokinin-1 (NK1) antagonist, FK888 (10 mg.kg-1 i.v.) pretreatment. Histamine-induced dye extravasation was not affected by L-NAME. LY83583 (2.5 and 7.5 mg.kg-1 i.v.) partially but significantly reduced SP-induced dye leakage. These results suggest that endogenous nitric oxide plays a role in neurokinin-1 receptor-mediated airway microvascular leakage, and presumably involves the guanylate cyclase pathway.

Incubation with IgE increases cholinergic neurotransmission in human airways in vitro.

Airway cholinergic hyperresponsiveness is frequently observed in asthmatic patients. Recent reports suggest the possible involvement of IgE in hyperresponsiveness, although the exact mechanism is still uncertain. In this study, we examined whether incubation with IgE could facilitate the cholinergic function in human airways. Bronchi were obtained from 20 patients undergoing lung resection. Cholinergic contractile responses were induced by electrical field stimulation (EFS) or exogenous acetylcholine (ACh), and they were assessed by isometric tension measurement. EFS-induced ACh release from cholinergic nerves was also measured by high performance liquid chromatography. Incubation with IgE significantly enhanced EFS-induced bronchial contraction and ACh release as compared with the values of the bronchi incubated with heat inactivated IgE (control) (p < 0.05, respectively), but it did not alter the contractile responses induced by exogenous ACh. Pretreatment with the muscarinic M2-receptor agonist pilocarpine reduced the EFS-induced ACh release in the control tissues (p < 0.05), but not in the tissues incubated with IgE. The M2-receptor antagonist methoctramine significantly enhanced the EFS-induced contraction in control bronchi (p < 0.05), but this augmentation was not observed in the tissues incubated with IgE. These results suggest that IgE itself can enhance cholinergic bronchial contraction via facilitation of ACh release from cholinergic nerves and that this augmentation is related to autoreceptor M2 dysfunction at nerve endings.

Endogenous nitric oxide modifies antigen-induced microvascular leakage in sensitized guinea pig airways.

To examine the role of endogenous nitric oxide in allergic airway inflammation, we investigated the effect of a nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (l-NAME), on antigen-induced airway microvascular leakage in actively sensitized guinea pigs by using Evans blue dye. Three weeks after sensitization with ovalbumin (10 micrograms), the tracheas were cannulated, and lungs were artificially ventilated. Animals were pretreated with atropine and propranolol (both 1 mg/kg, intravenously) to avoid neural modification. Ovalbumin inhalation (3 mg/ml, 1 minute) challenge caused significant microvascular leakage in all airways portions, which was significantly suppressed in a dose-dependent manner by pretreatment with intravenous injection of L-NAME (1 and 10 mg/kg) but not with the inactive enantiomer D-NAME (10 mg/kg). This inhibition by L-NAME was significantly reversed by co-administration of L-arginine (100 mg/kg, intravenously). Pretreatment with a vasoconstrictor, phenylephrine (20 micrograms/kg, intravenously), had no inhibitory effects on antigen-induced airway microvascular leakage despite increasing systemic blood pressure. Inhalation of representative mast cell-derived mediators, histamine (2 mg/ml, 1 minute) or leukotriene D4 (5 micrograms/ml, 1 minute), produced significant microvascular leakage in all airways. L-NAME (10 mg/kg, intravenously) partially but significantly inhibited leukotriene D4-induced leakage, whereas histamine-induced leakage was not affected. These results suggest that endogenous nitric oxide acts to increase airway microvascular leakage after airway allergic reaction.

Repeated allergen exposure enhances excitatory nonadrenergic noncholinergic nerve-mediated bronchoconstriction in sensitized guinea-pigs.

The effect of repeated allergen inhalation challenge on the airway excitatory nonadrenergic noncholinergic (e-NANC) nerve-mediated bronchoconstrictor response was studied in ovalbumin (OA) sensitized guinea-pigs. Three weeks after sensitization, OA inhalation, 0.03% for 3 min (challenged group), or saline inhalation (control group) was repeated every day for 4 weeks. The e-NANC nerve function was examined in vitro by means of isometric tension measurement of main bronchi. After pretreatment with atropine (10(-6) M) and propranolol (10(-6) M), we performed electrical field stimulation (EFS) or exogenous neurokinin A (NKA) administration. In the challenged group, EFS-induced main bronchial contraction was significantly greater than that of the control group (p < 0.05 or p < 0.01), but exogenous NKA-mediated responses were almost the same in both groups. The e-NANC-induced main bronchial contractions after EFS were enhanced by pretreatment with the neutral endopeptidase inhibitor, phosphoramidon, to the same degree in the control and challenged groups, indicating that the peptide degradation mechanisms were not impaired even in the challenged group. Substance P immunoreactivities in the lung of the challenged group were significantly higher than those of the control group. These results suggest that chronic airway inflammation after repeated allergen challenge increases excitatory nonadrenergic noncholinergic nerve function, possibly by enhancing sensory neuropeptide production and/or release.

Involvement of endogenous tachykinins in LTD4-induced airway responses.

Leukotriene D4-(LTD4) has been reported to cause tachykinin release from airway sensory nerves. However, the functional significance of endogenously released tachykinins in LTD4-mediated airway responses has not been fully clarified. The aim of this study was to investigate whether LTD4-induced airway responses are due, in part, to tachykinin release in guinea-pigs. Airway plasma exudation and bronchoconstriction were assessed by measuring extravasation of Evans blue dye and by mean pulmonary resistance (RL) in the presence of atropine (1 mg.kg-1 i.v.) and propranolol (1 mg.kg-1 i.v.), respectively. LTD4 (5 micrograms.mL-1 for 1 min) inhalation caused increase in plasma exudation and RL. Capsaicin pretreatment of animals to deplete sensory neuropeptides significantly inhibited LTD4-induced plasma exudation in the main bronchi, but not in the central (cIPA) and peripheral intrapulmonary airways (pIPA). Pretreatment with specific tachykinin neurokinin-1 (NK1)-receptor antagonists, FK 888 (10 mg.kg-1 i.v.) and CP 96345 (4 mg.kg-1 i.v.), also significantly reduced LTD4-induced plasma exudation in the main bronchi, and in the main bronchi and cIPA, respectively. However, these antagonists did not significantly affect the LTD4-induced increase in RL. In contrast, neurokinin-2 (NK2)-receptor antagonist, SR 48968 (0.3 mg.kg-1 i.v.), significantly inhibited the bronchoconstriction after LTD4-inhalation. These results suggest that leukotriene D4-induced bronchoconstriction and plasma exudation in guinea-pigs are, in part, due to tachykinin release from airway sensory nerves.

A neurokinin 1-receptor antagonist improves exercise-induced airway narrowing in asthmatic patients.

Recent reports suggest the involvement of vascular phenomena in exercise-induced asthma. Sensory neuropeptides, such as substance P (SP), which causes airway vascular dilatation and plasma leakage, have been demonstrated to play a role in hyperpnea-induced airway narrowing in animal studies. The purpose of this study was to investigate the importance of tachykinins in exercise-induced airway narrowing in patients with asthma using a selective neurokinin 1-receptor (NK1-receptor) antagonist, FK-888. In a double-blind, placebo-controlled, crossover trial, nine subjects with stable asthma were given FK-888 (2.5 mg) or placebo by inhalation 20 min before each exercise at a level previously demonstrated to cause a fall of at least 40% in specific airway conduction (SGaw). Inhalation of FK-888 had no significant effect on baseline SGaw. While the recovery from exercise-induced airway narrowing was significantly faster after treatment with FK-888 the area under the curve for SGaw during the 50 min after exercise was significantly reduced (p<0.05) and the time taken for the SGaw to recover to within 65% of baseline after exercise was also significantly shorter with FK-888 than the placebo (p<0.05). However, treatment with FK-888 did not significantly attenuate the maximal fall in SGaw. These results suggest that NK1-receptor-mediated mechanisms are involved in the recovery phase of exercise-induced airway narrowing. The possible mechanisms of these phenomena are discussed.

Angiotensin converting enzyme (ACE) inhibitor-induced cough and substance P.

BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors cause coughing in 5-10% of patients, but the exact mechanisms of this effect are still unclear. In the airways ACE degrades substance P so the cough mechanism may be related to this peptide. METHODS: Nine patients who developed a cough and five patients who did not develop a cough when taking the ACE inhibitor enalapril (2.5 or 5.0 mg/day) for hypertension were enrolled in the study. No subjects had respiratory disease and the respiratory function of all subjects was normal. One month after stopping enalapril, inhalation of hypertonic saline (4%) was performed using an ultrasonic nebuliser for 15-30 minutes to induce sputum. The concentration of substance P in the sputum sample was measured by radioimmunoassay. In four of the nine cases with a cough enalapril was given again for 1-2 weeks and the concentration of substance P in the induced sputum was again measured. RESULTS: One month after stopping enalapril the mean (SE) concentration of substance P in the sputum of the group with a cough was 16.6 (3.0) fmol/ml, significantly higher than that in the subjects without a cough (0.9 (0.5) fmol/ml). All four subjects in the group with a cough who were given a repeat dose of enalapril developed a cough again, but the concentrations of substance P in the induced sputum while taking enalapril (17.9 (3.2) fmol/ml) were similar to the values whilst off enalapril (20.0 (2.5) fmol/ml). CONCLUSIONS: The mechanisms of ACE inhibitor-induced coughing may involve substance P mediated airway priming. However, the final triggering of the ACE inhibitor-induced coughing is unlikely to be due to this peptide.

Allergic airway response and potassium channels: histamine release and airway inflammation.

The possible involvement of potassium (K) channels in allergic airway responses was examined in ovalbumin (OA)-sensitized guinea pigs. An ATP-sensitive K channel opener (BRL-38227) inhibited OA inhalation-induced bronchoconstriction and airway plasma leakage. BRL-38227 also had an inhibitory effect on exogenous histamine- and leukotriene-induced responses. In contrast, BRL-38227 did not affect OA-induced histamine release from minced lung tissues. Therefore, the ATP-sensitive K channel opener inhibits allergic bronchoconstriction and plasma leakage as a result of its effect on airway smooth muscle and postcapillary venules. Apamin, a small conductance Ca2+ -activated K channel (PK,Ca) blocker, significantly inhibited both OA-induced tracheal contraction and histamine release from lung tissues, suggesting that this compound reduces allergic airway responses via a mast cell stabilizing effect. We conclude that ATP-sensitive K channel opening and small conductance PK,Ca closure may be beneficial for preventing allergic airway responses.