Randomized clinical trial of chewing gum after laparoscopic colorectal resection.

BACKGROUND: Chewing gum may enhance intestinal motility after surgery. This trial studied whether chewing gum could lead to a further reduction in ileus in patients who had a laparoscopic colorectal resection and followed an enhanced recovery programme. METHODS: Patients undergoing laparoscopic colorectal resection were randomized to a control or intervention group. Patients in the control group received a standardized recovery programme. Patients in the intervention group were, in addition, given chewing gum three times daily from day 1 until discharge. Primary outcome measures were time to first flatus and first bowel motion. Time to feeling hungry and hospital stay were secondary outcome measures. RESULTS: Forty-one patients were randomized into each group. Thirty-seven patients underwent rectal resection and 45 had a colonic resection. Time to passage of flatus was shorter (18 versus 34 h; P = 0·007), first bowel motion occurred earlier (19 versus 44 h; P = 0·001) and time to feeling hungry was earlier (16 versus 25 h; P = 0·001) in the intervention group. There was no difference in the duration of hospital stay (5 days in the intervention group versus 5·5 days in the control group). Subgroup analyses revealed that the benefits of chewing gum were clearer in patients who had a colonic resection, with a shorter time to first flatus (20 versus 35 h; P = 0·043), first bowel motion (19 versus 53 h; P = 0·014) and feeling hungry (14 versus 40 h; P = 0·001). No adverse events were attributed to chewing gum. CONCLUSION: Chewing gum is a simple intervention that speeds intestinal transit in patients managed with a recovery programme after laparoscopic colorectal resection. REGISTRATION NUMBER: NCT02419586 (https://clinicaltrials.gov/).

Andrographolide protects against cigarette smoke-induced oxidative lung injury via augmentation of Nrf2 activity.

BACKGROUND AND PURPOSE: Cigarette smoke is a major cause for chronic obstructive pulmonary disease (COPD). Andrographolide is an active biomolecule isolated from the plant Andrographis paniculata. Andrographolide has been shown to activate nuclear factor erythroid-2-related factor 2 (Nrf2), a redox-sensitive antioxidant transcription factor. As Nrf2 activity is reduced in COPD, we hypothesize that andrographolide may have therapeutic value for COPD. EXPERIMENTAL APPROACH: Andrographolide was given i.p. to BALB/c mice daily 2h before 4% cigarette smoke exposure for 1h over five consecutive days. Bronchoalveolar lavage fluid and lungs were collected for analyses of cytokines, oxidative damage markers and antioxidant activities. BEAS-2B bronchial epithelial cells were exposed to cigarette smoke extract (CSE) and used to study the antioxidant mechanism of action of andrographolide. KEY RESULTS: Andrographolide suppressed cigarette smoke-induced increases in lavage fluid cell counts; levels of IL-1ß, MCP-1, IP-10 and KC; and levels of oxidative biomarkers 8-isoprostane, 8-OHdG and 3-nitrotyrosine in a dose-dependent manner. Andrographolide promoted inductions of glutathione peroxidase (GPx) and glutathione reductase (GR) activities in lungs from cigarette smoke-exposed mice. In BEAS-2B cells, andrographolide markedly increased nuclear Nrf2 accumulation, promoted binding to antioxidant response element (ARE) and total cellular glutathione level in response to CSE. Andrographolide up-regulated ARE-regulated gene targets including glutamate-cysteine ligase catalytic (GCLC) subunit, GCL modifier (GCLM) subunit, GPx, GR and heme oxygenase-1 in BEAS-2B cells in response to CSE. CONCLUSIONS: Andrographolide possesses antioxidative properties against cigarette smoke-induced lung injury probably via augmentation of Nrf2 activity and may have therapeutic potential for treating COPD.

Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins.

OBJECTIVE: To evaluate the efficacy of intensive lipid lowering with higher-dose statins. METHODS: Meta-analysis of seven randomized controlled trials comprising 50,972 participants. RESULTS: Mean follow-up was 3.1 years with mean age 63 years. Final LDL-C levels in intensive lipid-lowering group were 1.42-2.07 mmol/l compared to 2.1-3.5 mmol/l in the less intensive or control group. The intensive arm had significantly lower risks for stroke OR 0.80 (95% CI 0.71-0.89); major coronary events OR 0.74 (95% CI 0.65-0.83); cardiovascular disease (CVD) or coronary heart disease (CHD) deaths OR 0.84 (95% CI 0.74-0.95). Significantly higher liver enzyme abnormalities occurred in intensive group* (OR 3.96; 95% CI 2.08-7.53), but it was not associated with drug discontinuations (OR 1.20; 95% CI 0.88-1.64). CONCLUSION: In those at high risk of cardiovascular events, intensive lipid lowering with statins to LDL-C level <2.1 mmol/l significantly reduces risk of stroke, major coronary events and CVD or CHD deaths compared to LDL-C level ≥ 2.1 mmol/l. [*Correction added on 11 January 2011 after first online publication on 27 October 2010. The phrase, "Significantly higher liver enzyme abnormalities occurred in less intensive group", was amended to "Significantly higher liver enzyme abnormalities occurred in intensive group".].

Elevated plasma adiponectin levels in patients with chronic obstructive pulmonary disease.

BACKGROUND: Adiponectin is an anti-inflammatory adipokine that may play a role in chronic obstructive pulmonary disease (COPD) pathogenesis. OBJECTIVE: To investigate the relationship between adiponectin, interleukin (IL) 6, IL-8 and C-reactive protein (CRP) and COPD by evaluating these biomarkers in ever-smokers with or without the disease. METHOD: Plasma levels of adiponectin, IL-6, IL-8 and CRP were measured using commercially available kits in COPD patients (n = 71), healthy ever-smokers (n = 62) and non-smokers (n = 51). RESULTS: There were significant increases in plasma adiponectin, IL-6 and CRP in COPD patients (median [IQR] 4.39 microg/ml [2.68-6.98], 4.19 pg/ml [<2.40-6.40], 8.75 mg/l [4.26-40.63], respectively) compared to healthy ever-smokers (1.90 microg/ml [0.86-2.86], <2.40 pg/ml [<2.40-2.77], 3.71 mg/l [1.97-10.37 mg/l], respectively, P < 0.001) and non-smokers (1.76 microg/ml [1.34-2.52], <2.40 pg/ml [<2.40-2.78], 3.12 mg/l [2.11-5.71], respectively, P < 0.001). COPD patients had lower plasma IL-8 levels than healthy ever-smokers. Among ever-smokers with or without COPD, plasma adiponectin, IL-6 and CRP levels were inversely correlated with forced expiratory volume in 1 second (% predicted) after adjustment for age, body mass index, smoking status and pack-years. CONCLUSION: Our findings suggest that in COPD patients, adiponectin might be associated with COPD pathogenesis.

Perceptions and attitudes of rehabilitation medicine physicians on complementary and alternative medicine in Australia.

BACKGROUND: The growing demand for complementary and alternative medicine (CAM) is undeniable. We report a first study about the attitudes and behaviour of Australian rehabilitation physicians to CAM. METHODS: A prospective cross-sectional survey was undertaken to document the prevalence of, knowledge about and referrals to CAM therapies and their perceived effectiveness, by a sample of Australian rehabilitation physicians. RESULTS: Thirty-six out of 94 actively practising rehabilitation physicians from the Australasian Faculty of Rehabilitation Medicine, the Royal Australasian College of Physicians, replied to the survey, a response rate of 38%, and 85% reported familiarity with CAM, the most familiar therapies being acupuncture (80%), yoga (74%) and Tai-Chi (72%). CAM referral was reported in 84%, 38% personally used CAM, 94% of patients enquired about CAM therapies, 32% of respondents routinely enquired about CAM use. Age, sex and year of Fellowship were not associated with familiarity, personal use or frequency of patient enquiry about CAM. Those who reported to be very familiar with CAM were more likely to routinely enquire about CAM use (P = 0.028) and be more confident in prescribing certain CAM therapies (P < 0.05). CONCLUSION: Australian rehabilitation physicians report similar CAM referral rates to Canadian physiatrists and Australian general practitioners. The most commonly prescribed therapies were acupuncture, yoga and Tai-Chi. Almost all patients use CAM therapies, but only a minority of rehabilitation physicians enquires about CAM use on a regular basis. The latter may avoid potentially harmful drug interactions, as well as improve the quality of the physician-patient relationship.

Pathogenesis of COPD. Part II. Oxidative-antioxidative imbalance.

Chronic obstructive pulmonary disease (COPD) represents a serious global health problem that affects the aged. This State of the Art article summarises previous studies on oxidative-antioxidative imbalance in patients with stable COPD or in acute exacerbations. Recent literature in this field reports conflicting findings. Several studies on markers of oxidative stress have demonstrated increased production of oxidants in exhaled air, breath condensates or induced sputum. The primary defence against oxidants is endogenous antioxidants, which are altered in COPD. Some studies have demonstrated a marked decrease in plasma antioxidant capacity, while other studies have shown opposite findings. A few studies have shown higher erythrocyte superoxide dismutase (SOD) activity in COPD patients and healthy smokers than those in healthy non-smokers. In contrast, we found no differences in erythrocyte SOD activity and elevated erythrocyte catalase activity in Chinese patients with COPD compared with healthy smokers matched for age and pack-years smoked. Possible reasons for such discrepancies could be related to differences in inter-individual variations in antioxidant capacity as a result of different populations and also differences in methodologies between studies.

Relationship between glutathione S-transferase gene polymorphisms and enzyme activity in Hong Kong Chinese asthmatics.

BACKGROUND: Asthma is a disease associated with oxidative stress. The glutathione S-transferases (GST) are a group of enzymes that protect cells from oxidative stress. Functional genetic polymorphisms of GST genes (GSTT1, GSTM1 and GSTP1) have previously been reported. OBJECTIVE: To investigate the association of GST gene polymorphisms and its enzyme activity with the risk of asthma in Hong Kong Chinese adults. METHODS: An age- and smoking status-matched case-control study was carried out on 315 patients with asthma and 315 healthy controls. Genotyping was carried out on genomic DNA using the PCR and/or restriction fragment length polymorphism (PCR-RFLP). Plasma GST activity was measured by fluorometric assay. RESULTS: The distribution of various genotypes or alleles of the GSTT1, GSTM1 and GSTP1 was not significantly different between patients with asthma and healthy controls. The GSTM1 null genotype was found to be protective from the development of asthma in atopic subjects (odds ratios 0.55, 95% confidence interval 0.34-0.90; P=0.017). However, there was no association between GSTT1 and GSTM1 null genotypes and enzyme activity. GSTP1 codon 105 Val variants led to reduced plasma GST activity in healthy controls. Asthma patients had elevated plasma GST activity compared with healthy controls irrespective of their genotypes (P<0.001). CONCLUSION: Our data suggest that among atopic subjects, the GSTM1 null genotype is associated with a decreased risk for asthma despite increased level of plasma GST activity in asthma, but it could not distinguish whether this increase is a potentially protective compensatory effect or a pathogenic factor.

Polymorphisms and functional activity in superoxide dismutase and catalase genes in smokers with COPD.

Increased oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). This study investigated the risk of COPD and the substitution of alanine 16 with valine (Ala16Val) polymorphism of manganese-superoxide dismutase (Mn-SOD) and the cytosine to thymidine transition of nucleotide -262 (-262C>T) polymorphism of the catalase gene, and the activity of erythrocyte SOD and catalase. The subjects were stable COPD patient ever smokers (n = 165) and healthy controls, matched for age and cigarette consumption. Genotyping of Mn-SOD at Ala16Val and the catalase gene at -262C>T was performed, and the functional activity of SOD and catalase in erythrocytes determined. There were no significant differences in the distribution of the different genotypes or allele frequencies between patients and controls for both the Mn-SOD and catalase genes. Among healthy controls or COPD patients, no differences were observed in erythrocyte SOD and catalase activity, irrespective of genotype. Significantly higher erythrocyte catalase activity was found in COPD patients than in healthy controls. The T/T catalase genotype and Ala/Ala Mn-SOD genotype were uncommon in the present Chinese population. The increase in erythrocyte catalase activity in Chinese patients with chronic obstructive pulmonary disease probably indicates dysfunction of the oxidant/antioxidant defence system, but it is unclear whether this increase is compensatory or a pathogenic factor.

Polymorphisms of glutathione S-transferase genes and functional activity in smokers with or without COPD.

OBJECTIVE: To determine the role of polymorphisms of genes regulating glutathione S-transferase (GST) and its plasma GST activity in the pathogenesis of chronic obstructive pulmonary disease (COPD). DESIGN: Case-control study. METHODS: One hundred and sixty-three patients with stable COPD from several community or regional hospitals were matched for age and pack-years smoked with the same number of health controls from the general population. Each participant underwent an interview-based respiratory and smoking questionnaire, lung function testing and gave a blood sample. Genotyping was carried out using a polymerase chain reaction-based method for polymorphisms of glutathione S-transferase theta 1 (GSTT1), glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase P 1 (GSTP1) genes. Plasma GST activity was measured using the spectrofluorometric method. RESULTS: There were no significant differences in the distribution of various genotypes of polymorphisms of GSTT1, GSTM1 and GSTP1 between COPD patients and healthy controls. GST activity was significantly higher in patients compared with controls, irrespective of their different genotypes, and was not different between patients with different levels of airflow obstruction. CONCLUSION: Polymorphisms of GSTT1, GSTM1 and GSTP1 genes are unlikely to be involved in the pathogenesis of COPD in Chinese in Hong Kong and Southern China.

Disturbance of systemic antioxidant profile in nonsmall cell lung carcinoma.

The present study aimed to determine the alterations of antioxidant activities in erythrocytes from patients with nonsmall cell lung carcinoma (NSCLC). A comparative study of the systemic antioxidant activities in red blood cell lysate from subjects with NSCLC and healthy control subjects was conducted. The antioxidants catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured using chemical kinetic reactions under spectrophotometry. In total, 189 cases of mostly advanced-stage IIIB or stage IV NSCLC and 202 healthy controls were studied. In subjects with lung cancer, there was similar catalase activity, lower SOD activity (median (interquartile range) 13.4 (9.0-27.2) versus 48.7 (27.0-64.3) U x (ghaemoglobulin(Hb)(-1)), and higher GPx activity (175.2 (126.6-288.3) versus 49.2 (39.5-59.2) mU x (gHb)(-1)) compared with controls. The antioxidant activities in lung cancer subjects were not associated with age, sex, smoking status, or tumour cell types. However, more advanced disease (stage IV compared with stage IIIB) was associated with lower SOD activity. Using multivariable analysis, the presence of lung cancer independently predicted SOD and GPx activities. In conclusion, nonsmall cell lung carcinoma in Chinese subjects is associated with alterations in systemic antioxidant activities, which may play an important role in carcinogenesis.

Polymorphisms in manganese superoxide dismutase and catalase genes: functional study in Hong Kong Chinese asthma patients.

BACKGROUND: Reactive oxygen species may contribute to the pathogenesis of asthma. Functional genetic polymorphisms of antioxidant enzymes, superoxide dismutase (SOD) and catalase are good candidates for asthma susceptibility. OBJECTIVE: To investigate the association of the manganese-containing form of SOD (MnSOD) gene at amino acid position 16 (Val16Ala) and catalase gene in the promoter at A-21T and C-262T polymorphisms and asthma in a Hong Kong Chinese population. METHODS: The association study was conducted in a case-control design in asthma patients (n=251) and healthy controls (n=316) by genotyping. The functional significance was assessed by determining erythrocyte SOD and catalase activity. RESULTS: The Val allele of MnSOD at Val16Ala and the A allele of catalase gene at A-21T were not different between patients and controls, while the C allele of catalase gene at C-262T was found to be significantly different between patients and controls (P=0.033). The less frequent variant of catalase gene (-262T) was found to be protective from the development of asthma in a Hong Kong Chinese non-smoking population (adjusted odds ratio=0.35, 0.15-0.85; P=0.017). Asthma patients had elevated erythrocyte SOD and catalase activities in comparison with healthy controls (P<0.01). However, their activities were not associated with different genotypes within healthy controls or asthma patients. CONCLUSION: This is the first report showing that SOD and catalase functional activities are not associated with their respective genetic polymorphisms but related to the presence of asthma in a Hong Kong Chinese population.

Exhaled nitric oxide in bronchiectasis: the effects of inhaled corticosteroid therapy.

SETTING: While exhaled nitric oxide (eNO) levels are reduced by inhaled corticosteroid therapy in asthma, such treatment effect is unclear in bronchiectasis. DESIGN: Stable non-smoking bronchiectasis patients were randomised to receive either fluticasone (1 mg/daily) or identical placebo via the Accuhaler device. RESULTS: Sixty non-smoking patients (38 women; mean age 56.4 +/- 12.7 years) were recruited. Of these, half received inhaled fluticasone and half placebo therapy. eNO was measured using a chemiluminescence analyser at 0, 4, 12, 24, 36 and 52 weeks. There was no significant difference in eNO levels between fluticasone and placebo patients over the study period. There was no correlation between baseline eNO with age, FEV1, FVC, 24 h sputum volume or number of bronchiectatic segments. Patients with Pseudomonas aeruginosa (PA) infection, but not their counterparts, displayed a correlation between 0- and 52-week eNO levels. PA infection was associated with significantly lower eNO levels among the patients. CONCLUSIONS: Inhaled fluticasone therapy, despite being an effective anti-inflammatory agent, has no significant effect on eNO production, either at individual time points or over the entire 52-week profile, in bronchiectasis. It appears that eNO might not reflect the extent of airway inflammation in bronchiectasis.

Coriolus versicolor polysaccharide peptide slows progression of advanced non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths, and over 60% of patients present with advanced stages. Although polysaccharide peptides (PSP), isolated from the fungus Coriolus versicolor, have been reported to have anti-tumor effects, its clinical efficacy has not been properly evaluated. METHODS: Double-blind placebo-controlled randomized study to evaluate the effects of 28-day administration of PSP (Windsor Pharmaceutical, Hong Kong) on patients, who had completed conventional treatment for advanced NSCLC. RESULTS: Thirty-four patients, with no significant difference in their baseline demographic, clinical or tumor characteristics, or previous treatment regimes (P>0.05) were recruited into each of the PSP and control arms. After 28-day treatment, there was a significant improvement in blood leukocyte and neutrophil counts, serum IgG and IgM, and percent of body fat among the PSP, but not the control, patients (P<0.05). Although the evaluable PSP patients did not improve in NSCLC-related symptoms, there were significantly less PSP patients withdrawn due to disease progression, than their control counterparts (5.9 and 23.5%, respectively; P=0.04; OR 4.00). There was no reported adverse reaction attributable to the trial medications. CONCLUSION: PSP treatment appears to be associated with slower deterioration in patients with advanced NSCLC.

Mechanisms of interleukin 1beta-induced human airway smooth muscle hyporesponsiveness to histamine. Involvement of p38 MAPK NF-kappaB.

We have investigated the effect of IL-1beta on histamine H(1)-receptor (H(1)R)-mediated inositol phosphate (IP) accumulation in human airway smooth muscle cells (HASMC) and on histamine-induced contraction of human bronchial rings. Stimulation of HASMC for 24 h with IL-1beta resulted in significant loss of histamine-induced IP formation, which was associated with a reduction of histamine- induced contraction of IL-1beta-treated human bronchial rings. An inhibitor of NF-kappaB activation, pyrrolidine dithiocarbamate, and a p38 MAPK inhibitor, blocked the IL-1beta-induced H(1)R desensitization, whereas anisomycin, an SAPK/JNK and p38 MAPK activator, mimicked the effect of IL-1beta. IL-1beta has been demonstrated to induce cox-2 expression and PGE(2) synthesis. In our study, indomethacin a cox antagonist, completely inhibited the effect of IL-1beta on H(1)R, whereas exogenously added PGE(2) was able to desensitize H(1)R. Furthermore, H-89, a selective PKA inhibitor, antagonized the effect of IL-1beta. Here, we have demonstrated that IL-1beta desensitizes H(1)R, which involves the activation of p38 MAPK and NF-kappaB, leading to the expression of cox-2 and the synthesis of PGE(2). PGE(2) increases intracellular cAMP resulting in PKA activation, which phosphorylates and functionally uncouples H(1)R. Our results suggest that IL-1beta protects airway smooth muscle against histamine-induced contractile responses and that bronchial hyperreactivity to histamine is not associated with proinflammatory cytokine-induced enhancement in H(1)R signaling.

Chronic systemic administration of salmeterol to rats promotes pulmonary beta(2)-adrenoceptor desensitization and down-regulation of G(s alpha).

1. The aim of the present study was to examine the effects of chronic infusion of the long-acting agonist salmeterol on pulmonary beta(2)-adrenoceptor function in Sprague-Dawley rats in vivo and to elucidate the molecular basis of any altered state. 2. Systemic administration of rats with salmeterol for 7 days compromised the ability of salmeterol and prostaglandin E(2) (PGE(2)), given acutely by the intravenous route, to protect against ACh-induced bronchoconstriction when compared to rats treated identically with vehicle. 3. beta(1)- and beta(2)-adrenoceptor density was significantly reduced in lung membranes harvested from salmeterol-treated animals, which was associated with impaired salmeterol- and PGE(2)-induced cyclic AMP accumulation ex vivo. 4. Three variants of G(s alpha) that migrated as 42, 44 and 52 kDa peptides on SDS polyacrylamide gels were detected in lung membranes prepared from both groups of rats but the intensity of each isoform was markedly reduced in rats that received salmeterol. 5. The activity of cytosolic, but not membrane-associated, G-protein receptor-coupled kinase was elevated in the lung of salmeterol-treated rats when compared to vehicle-treated animals. 6. The ability of salmeterol, administered systemically, to protect the airways of untreated rats against ACh-induced bronchoconstriction was short-acting (t(off) approximately 45 min), which contrasts with its long-acting nature when given to asthmatic subjects by inhalation. 7. These results indicate that chronic treatment of rats with salmeterol results in heterologous desensitization of pulmonary G(s)-coupled receptors. In light of previous data obtained in rats treated chronically with salbutamol, we propose that a primary mechanism responsible for this effect is a reduction in membrane-associated G(s alpha). The short-acting nature of salmeterol, when administered systemically, and the reduction in beta-adrenoceptor number may be due to metabolism to a biologically-active, short-acting and non-selective beta-adrenoceptor agonist.

Contribution of upregulated airway endothelin-1 expression to airway smooth muscle and epithelial cell DNA synthesis after repeated allergen exposure of sensitized Brown-Norway rats.

Endothelin-1 is a potent bronchoconstrictor peptide with pro-inflammatory and growth-promoting properties. After exposure of sensitized Brown-Norway rats to six repeated ovalbumin exposures, there was an increase in pro-endothelin (ET)-1 messenger RNA compared with saline-exposed control rats 24 h after the final exposure (P < 0.01). ET-1 immunoreactivity was increased sixfold in the bronchial epithelium of the larger conducting airways in the repeated allergen-exposed rats (P < 0.001). After repeated allergen exposure, there were increased rates of DNA synthesis in the airway smooth muscle (ASM) cells (P < 0.001) and epithelial cells (P < 0. 001) compared with saline-exposed controls, as measured by bromodeoxyuridine incorporation. Treatment with a dual endothelin A and B (ET(A+B)) receptor antagonist caused a significant attenuation in both ASM (P < 0.001) and epithelial cell (P < 0.001) bromodeoxyuridine incorporation compared with the allergen-challenged and vehicle-treated group. The dual ET(A+B) antagonist attenuated eosinophil recruitment into the airways (P < 0. 05) but had no significant effect on increased bronchial reactivity to acetylcholine in allergen-exposed rats. Increased levels of ET-1 in the airways may contribute to inflammation and ASM and epithelial cell DNA synthesis after repeated allergen exposure. Such processes may underlie increased proliferation of resident cells leading to airway wall remodeling in asthmatics.

Transgenic overexpression of beta(2)-adrenergic receptors in airway epithelial cells decreases bronchoconstriction.

Airway epithelial cells express beta(2)-adrenergic receptors (beta(2)-ARs), but their role in regulating airway responsiveness is unclear. With the Clara cell secretory protein (CCSP) promoter, we targeted expression of beta(2)-ARs to airway epithelium of transgenic (CCSP-beta(2)-AR) mice, thereby mimicking agonist activation of receptors only in these cells. In situ hybridization confirmed that transgene expression was confined to airway epithelium, and autoradiography showed that beta(2)-AR density in CCSP-beta(2)-AR mice was approximately twofold that of nontransgenic (NTG) mice. Airway responsiveness measured by whole body plethysmography showed that the methacholine dose required to increase enhanced pause to 200% of baseline (ED(200)) was greater for CCSP-beta(2)-AR than for NTG mice (345 +/- 34 vs. 157 +/- 14 mg/ml; P < 0.01). CCSP-beta(2)-AR mice were also less responsive to ozone (0.75 ppm for 4 h) because enhanced pause in NTG mice acutely increased to 77% over baseline (P < 0.05) but remained unchanged in the CCSP-beta(2)-AR mice. Although both groups were hyperreactive to methacholine 6 h after ozone exposure, the ED(200) for ozone-exposed CCSP-beta(2)-AR mice was equivalent to that for unexposed NTG mice. These findings show that epithelial cell beta(2)-ARs regulate airway responsiveness in vivo and that the bronchodilating effect of beta-agonists results from activation of receptors on both epithelial and smooth muscle cells.

Beta-adrenergic agonists and bronchial hyperreactivity: role of beta2-adrenergic and tachykinin neurokinin-2 receptors.

BACKGROUND: beta(2)-Adrenergic agonists are the most widely used bronchodilators for the treatment of asthma. On the other hand, there is concern that excessive use of beta(2)-agonists may contribute to the exacerbation of asthma. However, the mechanism of such adverse effects of beta(2)-agonists is not completely clear. OBJECTIVE: The aim of this study was to assess the direct influence of beta(2)-agonists on airways by analyzing the effect of a beta(2)-agonist, fenoterol, on airway sensitivity in an animal model and on tachykinin neurokinin-2 receptor expression in bovine tracheal smooth muscle. METHODS: We performed an acetylcholine challenge test on ovalbumin sensitized guinea pigs that were exposed to daily inhalation of ovalbumin and fenoterol. We also investigated the effects of fenoterol on neurokinin-2 receptor messenger RNA and density with Northern blot analysis and receptor binding assay. RESULT: The increase of airway responsiveness and the decrease of beta(2)-adrenergic receptors were found in guinea pigs that were treated with fenoterol. There were time- and dose-dependent increases of neurokinin-2 receptor mRNA and of density in tracheal smooth muscle that was treated with fenoterol. CONCLUSION: This increased airway responsiveness, increased neurokinin-2 receptor expression, and decreased beta(2)-adrenergic receptor density may be relevant to asthma exacerbation.