Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma

BACKGROUND: Using guinea pig tracheal preparations, we have recently shown that endogenous arginase activity attenuates inhibitory nonadrenergic noncholinergic (iNANC) nerve-mediated airway smooth muscle relaxation by reducing nitric oxide (NO) production – due to competition with neuronal NO-synthase (nNOS) for the common substrate, L-arginine. Furthermore, in a guinea pig model of allergic asthma, airway arginase activity is markedly increased after the early asthmatic reaction (EAR), leading to deficiency of agonist-induced, epithelium-derived NO and subsequent airway hyperreactivity. In this study, we investigated whether increased arginase activity after the EAR affects iNANC nerve-derived NO production and airway smooth muscle relaxation. METHODS: Electrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5 – 16 Hz)-induced relaxation was measured in tracheal open-ring preparations precontracted to 30% with histamine in the presence of 1 μM atropine and 3 μM indomethacin. The contribution of NO to EFS-induced relaxation was assessed by the nonselective NOS inhibitor N(ω)-nitro-L-arginine (L-NNA, 100 μM), while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor N(ω)-hydroxy-nor-L-arginine (nor-NOHA, 10 μM). Furthermore, the role of substrate availability to nNOS was measured in the presence of exogenous L-arginine (5.0 mM). RESULTS: At 6 h after ovalbumin-challenge (after the EAR), EFS-induced relaxation (ranging from 3.2 ± 1.1% at 0.5 Hz to 58.5 ± 2.2% at 16 Hz) was significantly decreased compared to unchallenged controls (7.1 ± 0.8% to 75.8 ± 0.7%; P < 0.05 all). In contrast to unchallenged controls, the NOS inhibitor L-NNA did not affect EFS-induced relaxation after allergen challenge, indicating that NO deficiency underlies the impaired relaxation. Remarkably, the specific arginase inhibitor nor-NOHA normalized the impaired relaxation to unchallenged control (P < 0.05 all), which effect was inhibited by L-NNA (P < 0.01 all). Moreover, the effect of nor-NOHA was mimicked by exogenous L-arginine. CONCLUSION: The results clearly demonstrate that increased arginase activity after the allergen-induced EAR contributes to a deficiency of iNANC nerve-derived NO and decreased airway smooth muscle relaxation, presumably via increased substrate competition with nNOS

A microRNA-21-mediated SATB1/S100A9/NF-κB axis promotes chronic obstructive pulmonary disease pathogenesis.

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Reference values for exhaled nitric oxide (reveno) study

BACKGROUND: Despite the widespread use of fractional exhaled nitric oxide (FE(NO)) as a biomarker of airways inflammation, there are no published papers describing normal FE(NO )values in a large group of healthy adults. OBJECTIVE: The aim of this study was to establish adult FE(NO )reference values according to the international guidelines. METHODS: FE(NO )was measured in 204 healthy, non-smoking adults with normal spirometry values using the on-line single-breath technique, and the results were analysed chemiluminescently. RESULTS: The main result of the study was the significant difference in FE(NO )values between men and women, thus indicating that gender-based reference FE(NO )values are necessary. The FE(NO )levels obtained at expiratory flows of 50 ml/s ranged from 2.6 to 28.8 ppb in men, and from 1.6 to 21.5 ppb in women. CONCLUSION: We propose reference FE(NO )values for healthy adult men and women that could be used for clinical and research purposes

Bronchial Responsiveness Is Related to Increased Exhaled NO (FENO) in Non-Smokers and Decreased FENO in Smokers

Rationale Both atopy and smoking are known to be associated with increased bronchial responsiveness. Fraction of nitric oxide (NO) in the exhaled air (FENO), a marker of airways inflammation, is decreased by smoking and increased by atopy. NO has also a physiological bronchodilating and bronchoprotective role. Objectives To investigate how the relation between FENO and bronchial responsiveness is modulated by atopy and smoking habits. Methods Exhaled NO measurements and methacholine challenge were performed in 468 subjects from the random sample of three European Community Respiratory Health Survey II centers: Turin (Italy), Gothenburg and Uppsala (both Sweden). Atopy status was defined by using specific IgE measurements while smoking status was questionnaire-assessed. Main Results Increased bronchial responsiveness was associated with increased FENO levels in non-smokers (p = 0.02) and decreased FENO levels in current smokers (p = 0.03). The negative association between bronchial responsiveness and FENO was seen only in the group smoking less &lt;10 cigarettes/day (p = 0.008). Increased bronchial responsiveness was associated with increased FENO in atopic subjects (p = 0.04) while no significant association was found in non-atopic participants. The reported interaction between FENO and smoking and atopy, respectively were maintained after adjusting for possible confounders (p-values&lt;0.05). Conclusions The present study highlights the interactions of the relationship between FENO and bronchial responsiveness with smoking and atopy, suggesting different mechanisms behind atopy- and smoking-related increases of bronchial responsiveness

Exhaled breath condensate pH as a biomarker of COPD severity in ex-smokers

Endogenous airway acidification, as assessed by exhaled breath condensate (EBC) pH, is present in patients with stable COPD. The aim of this study was to measure EBC pH levels in a large cohort of COPD patients and to evaluate associations with functional parameters according to their smoking status

Arginase attenuates inhibitory nonadrenergic noncholinergic nerve-induced nitric oxide generation and airway smooth muscle relaxation

BACKGROUND: Recent evidence suggests that endogenous arginase activity potentiates airway responsiveness to methacholine by attenuation of agonist-induced nitric oxide (NO) production, presumably by competition with epithelial constitutive NO synthase for the common substrate, L-arginine. Using guinea pig tracheal open-ring preparations, we now investigated the involvement of arginase in the modulation of neuronal nitric oxide synthase (nNOS)-mediated relaxation induced by inhibitory nonadrenergic noncholinergic (iNANC) nerve stimulation. METHODS: Electrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5 – 16 Hz)-induced relaxation was measured in tracheal preparations precontracted to 30% with histamine, in the presence of 1 μM atropine and 3 μM indomethacin. The contribution of NO to the EFS-induced relaxation was assessed by the nonselective NOS inhibitor L-NNA (0.1 mM), while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor nor-NOHA (10 μM). Furthermore, the role of substrate availability to nNOS in EFS-induced relaxation was measured in the presence of various concentrations of exogenous L-arginine. RESULTS: EFS induced a frequency-dependent relaxation, ranging from 6.6 ± 0.8% at 0.5 Hz to 74.6 ± 1.2% at 16 Hz, which was inhibited with the NOS inhibitor L-NNA by 78.0 ± 10.5% at 0.5 Hz to 26.7 ± 7.7% at 8 Hz (P < 0.01 all). In contrast, the arginase inhibitor nor-NOHA increased EFS-induced relaxation by 3.3 ± 1.2-fold at 0.5 Hz to 1.2 ± 0.1-fold at 4 Hz (P < 0.05 all), which was reversed by L-NNA to the level of control airways in the presence of L-NNA (P < 0.01 all). Similar to nor-NOHA, exogenous L-arginine increased EFS-induced airway relaxation (P < 0.05 all). CONCLUSION: The results indicate that endogenous arginase activity attenuates iNANC nerve-mediated airway relaxation by inhibition of NO generation, presumably by limiting L-arginine availability to nNOS

Exhaled nitric oxide in a population-based study of Southern California Schoolchildren

<p>Abstract</p> <p>Background</p> <p>Determinants of exhaled nitric oxide (FeNO) need to be understood better to maximize the value of FeNO measurement in clinical practice and research. Our aim was to identify significant predictors of FeNO in an initial cross-sectional survey of southern California schoolchildren, part of a larger longitudinal study of asthma incidence.</p> <p>Methods</p> <p>During one school year, we measured FeNO at 100 ml/sec flow, using a validated offline technique, in 2568 children of age 7–10 yr. We estimated online (50 ml/sec flow) FeNO using a prediction equation from a separate smaller study with adjustment for offline measurement artifacts, and analyzed its relationship to clinical and demographic characteristics.</p> <p>Results</p> <p>FeNO was lognormally distributed with geometric means ranging from 11 ppb in children without atopy or asthma to 16 ppb in children with allergic asthma. Although effects of atopy and asthma were highly significant, ranges of FeNO for children with and without those conditions overlapped substantially. FeNO was significantly higher in subjects aged > 9, compared to younger subjects. Asian-American boys showed significantly higher FeNO than children of all other sex/ethnic groups; Hispanics and African-Americans of both sexes averaged slightly higher than non-Hispanic whites. Increasing height-for-age had no significant effect, but increasing weight-for-height was associated with decreasing FeNO.</p> <p>Conclusion</p> <p>FeNO measured offline is a useful biomarker for airway inflammation in large population-based studies. Further investigation of age, ethnicity, body-size, and genetic influences is needed, since they may contribute to substantial variation in FeNO.</p

Prevention of bronchial hyperreactivity in a rat model of precapillary pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>The development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones.</p> <p>Methods</p> <p>Five groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezosentan via an intraperitoneally implemented osmotic pump, or by orally administered sildenafil. An additional group underwent sham surgery. Four weeks later, the lung responsiveness to increasing doses of an intravenous infusion of methacholine (2, 4, 8 12 and 24 μg/kg/min) was determined by using the forced oscillation technique to assess the airway resistance (Raw).</p> <p>Results</p> <p>BHR developed in the untreated rats, as reflected by a significant decrease in ED₅₀, the equivalent dose of methacholine required to cause a 50% increase in Raw. All drugs tested prevented the development of BHR, iloprost being the most effective in reducing both the systolic pulmonary arterial pressure (Ppa; 28%, p = 0.035) and BHR (ED₅₀= 9.9 ± 1.7 vs. 43 ± 11 μg/kg in ACS control and iloprost-treated rats, respectively, p = 0.008). Significant correlations were found between the levels of Ppa and ED₅₀(R = -0.59, p = 0.016), indicating that mechanical interdependence is primarily responsible for the development of BHR.</p> <p>Conclusions</p> <p>The efficiency of such treatment demonstrates that re-establishment of the balance of constrictor/dilator mediators via various signalling pathways involved in PHT is of potential benefit for the avoidance of the development of BHR.</p

IgE sensitisation in relation to flow-independent nitric oxide exchange parameters

BACKGROUND: A positive association between IgE sensitisation and exhaled NO levels has been found in several studies, but there are no reports on the compartment of the lung that is responsible for the increase in exhaled NO levels seen in IgE-sensitised subjects. METHODS: The present study comprised 288 adult subjects from the European Community Respiratory Health Survey II who were investigated in terms of lung function, IgE sensitisation (sum of specific IgE), smoking history and presence of rhinitis and asthma. Mean airway tissue concentration of NO (Caw(NO)), airway transfer factor for NO (Daw(NO)), mean alveolar concentration of NO (Calv(NO)) and fractional exhaled concentration of NO at a flow rate of 50 mL s(-1 )(FE(NO 0.05)) were determined using the extended NO analysis. RESULTS: IgE-sensitised subjects had higher levels (geometric mean) of FE(NO 0.05 )(24.9 vs. 17.3 ppb) (p < 0.001), Daw(NO )(10.5 vs. 8 mL s(-1)) (p = 0.02) and Caw(NO )(124 vs. 107 ppb) (p < 0.001) and positive correlations were found between the sum of specific IgE and FE(NO 0.05), Caw(NO )and Daw(NO )levels (p < 0.001 for all correlations). Sensitisation to cat allergen was the major determinant of exhaled NO when adjusting for type of sensitisation. Rhinitis and asthma were not associated with the increase in exhaled NO variables after adjusting for the degree of IgE sensitisation. CONCLUSION: The presence of IgE sensitisation and the degree of allergic sensitisation were related to the increase in airway NO transfer factor and the increase in NO concentration in the airway wall. Sensitisation to cat allergen was related to the highest increases in exhaled NO parameters. Our data suggest that exhaled NO is more a specific marker of allergic inflammation than a marker of asthma or rhinitis