Carbon monoxide levels after inhalation from new generation heated tobacco products.

Heated tobacco products (HTPs) are new tech devices that release nicotine and other volatile compounds into an inhalable aerosol by heating the tobacco. At their operating temperatures, tobacco combustion is unlikely.The aim of this randomized cross-over study was to measure the exposure levels of the combustion marker, carbon monoxide in the exhaled breath (eCO) of subjects after use of two HTPs and to compare these levels with participants' own brand of cigarettes.A total of 12 healthy smokers who reported smoking ≥10 conventional cigarettes per day for at least 5 years took part in the study. Product administration consisted of a first round of 10 puffs, which was followed by an identical second round after a 5 min pause in between rounds. After obtaining a baseline eCO value, this measure was recorded at 5, 10, 15, 30, and 45 min after the first puff of the first round. In contrast to combustible cigarettes, no eCO elevations were observed in the exhaled breath after use of the HTPs under investigation in any of the study participants.

Airway responsiveness to adenosine after a single dose of fluticasone propionate discriminates asthma from COPD.

BACKGROUND: Regular treatment with inhaled corticosteroids (ICS) is known to reduce airway hyperresponsiveness (AHR) to adenosine 5'-monophosphate (AMP) in asthma even after a single dose of fluticasone propionate (FP). AIM: To determine whether this rapid protective effect of a single dose of FP is also present in COPD. METHODS: 23 mild asthmatic and 24 COPD subjects with documented AHR to both AMP and methacholine took part in a randomized, double-blind, placebo-controlled, crossover study to measure AHR to inhaled AMP and methacholine 2 h after either 1000 µg FP or matched placebo. RESULTS: In subjects with asthma, 1000 µg FP in a single dose significantly attenuated the constrictor response to AMP, geometric mean (range) PC20AMP values increasing from a 19.2 (1.3-116.3) to 81.5 (9.6-1600.0) (p < 0.001; post-placebo vs post-FP) mg/ml. Change in the airways response to inhaled AMP after FP was well within test variability in patients with COPD, with PC20AMP values 59.6 (11.3-183.9) and 76.3 (21.0-445.3) (p = 0.022; post-placebo vs post-FP) mg/ml. Additionally, FP failed to significantly attenuate the bronchial response to methacholine in both asthma and COPD subjects. A change in doubling dilution, between placebo and following a single dose of FP, in AMP had a better sensitivity and specificity of 95.8% and 65.2%, compared to methacholine of 79.2% and 43.5% respectively in delineating between COPD and asthma. CONCLUSION: A single dose of 1000 µg FP rapidly improves AHR to AMP in asthmatics but not in COPD subjects. This may provide a convenient way by which provocation challenge with inhaled AMP may help in discriminating asthma from COPD.

Beclomethasone dipropionate attenuates airways hyperresponsiveness to neurokinin A and histamine in asthma.

BACKGROUND: Inhaled corticosteroids (ICS) are the most effective anti-inflammatory agents available for the treatment of asthma but they produce only modest effects on airway inflammation and non-specific bronchial hyperresponsiveness (BHR). However, little is known about the possibility that treatment with ICS might cause additional protection on BHR to inhaled tachykinins such as neurokinin A (NKA). OBJECTIVE: Therefore, we compared the effects of beclomethasone dipropionate (BDP) on the degree of BHR to inhaled histamine and NKA in a double-blind, controlled, cross-over study of asthmatic patients. METHODS: Patients attended the laboratory before and after each 6 weeks treatment period to undertake concentration-response studies with histamine and NKA. Bronchial responsiveness to both funs was expressed as the provocative concentration producing a 20% decrease in FEV(1) from baseline (PC(20)). RESULTS: BDP therapy attenuated the constrictor response to both agonists to a similar degree, their geometric mean (range) PC(20) values increasing from 0.47 (0.21-1.41) mg/ml to 2.43 (0.51-4.50) mg/ml (P<0.01, post-salb vs. post-BDP treatment) and from 101.7 (27.3-356.1) microg/ml to 666.7 (151.5-1,000) microg/ml (P<0.01, post-salb vs. post-BDP treatment) for histamine and NKA, respectively. CONCLUSION: Airway responsiveness to histamine and NKA is reduced by BDP to the same extent. As a result of these findings, provocation with NKA is unlikely to provide additional useful information in the assessment of airway inflammation in asthma.

Effect of acute exacerbations on circulating endothelial, clotting and fibrinolytic markers in COPD patients.

Patients with chronic obstructive pulmonary disease (COPD) are prone to clinical exacerbations that are associated with increased airway inflammation, a potent pro-thrombotic stimulus. Limited information is available on the mechanisms underlying the putative alterations of the endothelial-coagulative system during acute exacerbations. The aim was to investigate whether the activation of the endothelial-coagulative system occurs in association with the acute inflammatory response of COPD exacerbation. We monitored the blood levels of surrogate markers of inflammation: interleukin-6 (IL-6); endothelium damage: von Willebrand's factor (vWF); clotting activation: D-dimer (D-D), and prothrombin fragment 1+2 (F1+2); fibrinolytic response: plasminogen activator inhibitor 1 (PAI-1), in COPD subjects, during hospital admission and after clinical resolution. In 30 COPD subjects, IL-6, vWF, D-D and F1+2 levels were elevated during exacerbation and decreased significantly at clinical stability (IL-6, p = 0.005; vWF, p < 0.001; D-D, p < 0.001; F1+2, p < 0.001). PAI-1 levels did not change at exacerbation compared to clinically stable situations. Positive correlations were observed between several of the markers measured. Elevation of IL-6, vWF, D-D and F1+2 levels during COPD exacerbations implies a strict association between acute inflammation, endothelial activation and clotting initiation. This was not associated with a change in PAI-1, implying an increase in the fibrinolytic response to inflammation. The pro-thrombotic nature of COPD exacerbations sustained by enhanced clotting activation appears to be mitigated by excessive fibrinolysis.

Inhibitory effect of a leukotriene receptor antagonist (montelukast) on neurokinin A-induced bronchoconstriction.

BACKGROUND: Tachykinins are potent contractors of human airways producing a dose-related bronchoconstriction when administered by means of inhalation to asthmatic subjects. OBJECTIVE: The aim of this study was to examine the effective role played by leukotrienes (LTs) in neurokinin A (NKA)-induced bronchoconstriction in asthmatic patients. METHODS: To address this question, we investigated the protective effect of a selective cysteinyl LT receptor antagonist, montelukast, against inhaled NKA and determined LTE(4) excretion in the urine. RESULTS: Inhaled NKA in the absence of any drug treatment produced a concentration-related bronchospasm with a geometric mean provocative concentration required to produce a 15% decrease in FEV(1) from the postsaline baseline value (PC(15)) value of 290.9 microg/mL (+SE, 407.1 microg/mL; -SE, 207.84 microg/mL). Montelukast pretreatment significantly increased (P <.01) the PC(15) NKA value (708.8 microg/mL; +SE, 890.47 microg/mL; -SE, 564.15 microg/mL) in comparison with placebo (394.4 microg/mL; +SE, 491.88 microg/mL; -SE, 248.16 microg/mL) and produced a shift of the NKA concentration-response curve to the right in all the subjects studied. When compared with placebo, montelukast did not have a significant protective effect against methacholine challenge; the geometric mean PC(15) values obtained were 0.87 and 0.96 mg/mL with placebo and montelukast, respectively. Although we have not observed any increase in urinary LTE(4) excretion after NKA inhalation, we have shown that pretreatment of asthmatic subjects with montelukast elicits a significant protection against NKA-induced bronchoconstriction. CONCLUSION: In asthmatic subjects NKA-induced bronchoconstriction is indirectly caused by the release of LTs, and this mechanism could explain some of the antiasthmatic and anti-inflammatory effects of LT antagonists.

Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation.

BACKGROUND: Previous studies have shown that inhaled heparin attenuated the airway responses to allergen, exercise, and AMP bronchial provocation, possibly through an inhibition of mast cell activation. OBJECTIVE: The aim of this study was to provide the evidence of in vivo inhibition of human mast cell activation by heparin in a noninvasive model. METHODS: Nine atopic and 6 nonatopic subjects received placebo and unfractionated heparin sodium (5000 IU/mL) 15 minutes before an AMP nasal provocation in a double-blind crossover study design. The nasal lavage was collected from these subjects before or 3, 5, 15, or 30 minutes after the AMP nasal challenge, and concentrations of histamine and tryptase in the nasal lavage were measured. RESULTS: AMP nasal provocation produced considerable sneezing and induced a transient increase in histamine and tryptase release, with peak values achieved at 3 to 5 minutes after the challenge in all atopic subjects. Compared with placebo, inhaled heparin significantly attenuated the release of histamine and tryptase induced by AMP challenge (P=.012 and.004, respectively). Moreover, the AMP-induced sneezing was also inhibited by pretreatment with heparin (P=.016). In nonatopic subjects, AMP did not induce a significant increase in histamine and tryptase release on placebo-treated or heparin-treated days. CONCLUSION: These data suggest that AMP nasal provocation and AMP bronchial provocation cause mast cell mediator release in a similar fashion. In addition, the data support the hypothesis that inhaled heparin plays a protective role against AMP provocation by inhibition of mast cell activation.

Induction of the epidermal growth factor receptor and its ligands in nasal epithelium by ozone.

BACKGROUND: Ozone is a photochemical oxidant pollutant that is an important public health hazard. Although the inflammatory response that occurs in response to ozone inhalation is well characterized, the mechanisms underlying epithelial cell activation are not well understood. OBJECTIVE: Because the epidermal growth factor receptor (EGFR) is a central regulator of epithelial function, we tested the hypothesis that nasal epithelial cells respond to ozone-induced oxidant stress by modulating expression of the EGFR and its ligands, EGF and transforming growth factor-alpha (TGF-alpha). METHODS: Normal volunteers were exposed to air or 400 parts per billion ozone for 2 hours, and then nasal biopsy specimens were harvested 6 hours later for immunohistochemical analysis of EGFR, EGF, and TGF-alpha. Nasal epithelial cell cultures were exposed in vitro to ozone or TNF-alpha; mediator release was measured by ELISA and cellular EGFR expression by immunoblotting and fluorescence-activated cell sorting analysis. RESULTS: Epithelial expression of the EGFR, EGF, and TGF-alpha were all significantly (P <.05) increased in the nasal biopsy specimens after ozone exposure, and there was a significant positive correlation between EGFR expression and the increase in neutrophil numbers in the nasal epithelium (P =.001, rho = 0.87). In vitro exposure of primary nasal epithelial cell cultures to ozone had no effect on EGFR expression, even though IL-8 release was enhanced. In contrast, exposure to TNF-alpha caused EGFR levels to increase significantly. CONCLUSION: These data suggest that the ozone-induced increase in EGFR expression observed in vivo is indirect, perhaps mediated by neutrophil-derived TNF-alpha.

Changes in sputum counts and airway hyperresponsiveness after budesonide: monitoring anti-inflammatory response on the basis of surrogate markers of airway inflammation.

BACKGROUND: Airway hyperresponsiveness (AHR) to pharmacologic stimuli and sputum eosinophils might be useful in the individual adjustment of long-term asthma management. However, it is not clear whether inhaled glucocorticosteroids (GCSs) provide greater protection against specific surrogate markers of airways inflammation than other means. In addition, detailed longitudinal assessment of changes in airway response with inhaled GCSs has never been carried out. OBJECTIVES: We compared changes in AHR to inhaled methacholine and adenosine 5'-monophosphate (AMP) after budesonide treatment in a randomized, double-blind, placebo-controlled, crossover study of patients with mild-to-moderate asthma. Subsequently, we undertook a separate study to examine the time course of the changes in AHR in more detail and the changes in sputum cell counts in relation to budesonide treatment. METHODS: In the phase 1 of the study, patients undertook bronchial provocation studies with increasing doubling concentrations of methacholine (0.06 to 16 mg/mL) and AMP (3.125 to 800 mg/mL) before and after budesonide 0.8 mg/daily for 3 weeks. The bronchial responses to the inhaled agonists were expressed as the provocative concentration causing a 20% decline in FEV(1) (PC(20)). In phase 2 of the study, patients attended the laboratory on 12 separate occasions to investigate changes in PC(20) methacholine, PC(20) AMP, and sputum cell counts before, during, and after withdrawal of therapy with inhaled budesonide 0.8 mg/daily for 6 weeks. RESULTS: Budesonide treatment for 3 weeks significantly attenuated the constrictor response by 0.8 +/- 0.3 doubling doses for methacholine and by 2.6 +/- 0.5 doubling doses for AMP. These changes were significantly different from each other (P =.003). Significant variation in PC(20) methacholine (P <.05) value, PC(20) AMP (P <.001) value, percentage of sputum eosinophils (P <.001), and percentage of sputum epithelial cells (P <.001) were observed throughout the longitudinal assessment of changes in airway response to budesonide. Compared with the other surrogate markers, PC(20) AMP appears to be useful in promptly detecting early inflammatory changes of the asthmatic airways; a significant change of 1.6 +/- 0.3, 2.2 +/- 0.3, and 2.8 +/- 0.3 doubling doses of PC(20) AMP was observed at 1, 4, and 6 weeks, respectively, in the course of budesonide treatment. CONCLUSIONS: The present findings underline the exquisite selectivity of diverse surrogate markers of airway inflammation in response to inhaled budesonide. When compared with that to the other markers, AHR to inhaled AMP is an early and sensitive indicator of the beneficial anti-inflammatory effects of topical GCSs.