Pulmonary Disease and Age at Immigration among Hispanics. Results from the Hispanic Community Health Study/Study of Latinos.

RATIONALE: Asthma has been reported to be more prevalent among Hispanics of Puerto Rican heritage than among other Hispanics and among Hispanics born in the United States or who immigrated as children than among those who came as adults; however, direct comparisons across Hispanic groups are lacking. OBJECTIVES: To test whether asthma is more prevalent among Hispanics of Puerto Rican heritage than among other Hispanic groups, whether asthma is associated with age of immigration, and whether chronic obstructive pulmonary disease varies by heritage in a large, population-based cohort of Hispanics in the United States. METHODS: The Hispanic Community Health Study/Study of Latinos researchers recruited a population-based probability sample of 16,415 Hispanics/Latinos, 18-74 years of age, in New York City, Chicago, Miami, and San Diego. Participants self-reported Puerto Rican, Cuban, Dominican, Mexican, Central American, or South American heritage; birthplace; and, if relevant, age at immigration. A respiratory questionnaire and standardized spirometry were performed with post-bronchodilator measures for those with airflow limitation. MEASUREMENTS AND MAIN RESULTS: The prevalence of physician-diagnosed asthma among Puerto Ricans (36.5%; 95% confidence interval, 33.6-39.5%) was higher than among other Hispanics (odds ratio, 3.9; 95% confidence interval, 3.3-4.6). Hispanics who were born in the mainland United States or had immigrated as children had a higher asthma prevalence than those who had immigrated as adults (19.6, 19.4, and 14.1%, respectively; P < 0.001). Current asthma, bronchodilator responsiveness, and wheeze followed similar patterns. Chronic obstructive pulmonary disease prevalence was higher among Puerto Ricans (14.1%) and Cubans (9.8%) than among other Hispanics (<6.0%), but it did not vary across Hispanic heritages after adjustment for smoking and prior asthma (P = 0.22), by country of birth, or by age at immigration. CONCLUSIONS: Asthma was more prevalent among Puerto Ricans, other Hispanics born in the United States, and those who had immigrated as children than among other Hispanics. In contrast, the higher prevalence of chronic obstructive pulmonary disease among Puerto Ricans and Cubans was largely reflective of differential smoking patterns and asthma.

Vegetable glycerin e-cigarette aerosols cause airway inflammation and ion channel dysfunction.

Vegetable glycerin (VG) and propylene glycol (PG) serve as delivery vehicles for nicotine and flavorings in most e-cigarette (e-cig) liquids. Here, we investigated whether VG e-cig aerosols, in the absence of nicotine and flavors, impact parameters of mucociliary function in human volunteers, a large animal model (sheep), and air-liquid interface (ALI) cultures of primary human bronchial epithelial cells (HBECs). We found that VG-containing (VG or PG/VG), but not sole PG-containing, e-cig aerosols reduced the activity of nasal cystic fibrosis transmembrane conductance regulator (CFTR) in human volunteers who vaped for seven days. Markers of inflammation, including interleukin-6 (IL6), interleukin-8 (IL8) and matrix metalloproteinase-9 (MMP9) mRNAs, as well as MMP-9 activity and mucin 5AC (MUC5AC) expression levels, were also elevated in nasal samples from volunteers who vaped VG-containing e-liquids. In sheep, exposures to VG e-cig aerosols for five days increased mucus concentrations and MMP-9 activity in tracheal secretions and plasma levels of transforming growth factor-beta 1 (TGF-ß1). In vitro exposure of HBECs to VG e-cig aerosols for five days decreased ciliary beating and increased mucus concentrations. VG e-cig aerosols also reduced CFTR function in HBECs, mechanistically by reducing membrane fluidity. Although VG e-cig aerosols did not increase MMP9 mRNA expression, expression levels of IL6, IL8, TGFB1, and MUC5AC mRNAs were significantly increased in HBECs after seven days of exposure. Thus, VG e-cig aerosols can potentially cause harm in the airway by inducing inflammation and ion channel dysfunction with consequent mucus hyperconcentration.

Rapid nongenomic actions of inhaled corticosteroids on long-acting ß(2)-agonist transport in the airway.

Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting ß(2)-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the non-charged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid-sensitive disposition mechanism for cationic long-acting ß(2)-agonist bronchodilators in the airway. Potency rank order and other 'classical' features of anti-inflammatory effects do not apply to inhaled corticosteroids' rapid drug transport actions.

Airway endothelial dysfunction in asthma and chronic obstructive pulmonary disease: a challenge for future research.

Endothelial dysfunction in the extrapulmonary circulation has been linked to cardiovascular disease. Recent investigations have revealed that in the airway circulation, cigarette smoking, chronic obstructive pulmonary disease (COPD), and asthma are also accompanied by endothelial dysfunction. Inhaled glucocorticosteroids can partially or fully restore normal endothelium-dependent vasodilation in these conditions, thereby identifying the airway endothelium as a novel therapeutic target in the treatment of airway disease. The role of the defective endothelium-dependent vasodilation in the pathophysiology in asthma and COPD is still subject to speculation. However, there appears to be an association between COPD and extrapulmonary vascular dysfunction, and the possibility exists that the use of inhaled glucocorticosteroids has a beneficial effect on cardiovascular disease in COPD as suggested by database studies showing that inhaled glucocorticosteroids reduce the incidence of nonfatal and fatal cardiovascular events in COPD.

Rapid corticosteroid effect on beta(2)-adrenergic airway and airway vascular reactivity in patients with mild asthma.

BACKGROUND: Long-term glucocorticoid therapy has been suggested to improve airway and airway vascular smooth muscle responsiveness to inhaled beta(2)-agonists in patients with asthma. OBJECTIVE: We sought to assess whether a single dose of an inhaled glucocorticoid acutely potentiates beta(2)-adrenergic airway and airway vascular smooth muscle reactivity in asthma. METHODS: In 10 asthmatic and 10 healthy subjects, airway blood flow and FEV(1) were measured before and 30 minutes after fluticasone or placebo inhalation and 15 minutes after the subsequent inhalation of racemic albuterol (0.6 mg or 1.25 mg) or (R)-albuterol (0.3 mg or 0.6 mg). RESULTS: In healthy subjects all albuterol formulations increased airway blood flow equally after placebo or fluticasone pretreatment. In asthmatic subjects airway blood flow response was blunted after placebo and acutely restored after fluticasone pretreatment. Fluticasone pretreatment did not increase FEV(1) responses to any albuterol formulation, except 0.6 mg racemic albuterol. CONCLUSION: A single dose of an inhaled glucocorticoid restores beta(2)-adrenergic airway vasodilator responses in patients with mild asthma. The mechanism of this rapid glucocorticoid effect remains to be clarified.

Effect of an inhaled glucocorticoid on endothelial function in healthy smokers.

Cigarette smoking is associated with attenuated endothelium-dependent vasodilation (endothelial dysfunction) in the systemic circulation, including the airway circulation. We wished to determine whether an inhaled corticosteroid could restore endothelial function in the airway of lung-healthy current smokers, ex-smokers, and nonsmokers. We measured baseline airway blood flow (Qaw) and Qaw reactivity to inhaled albuterol as an index of endothelium-dependent vasodilation and to sublingual nitroglycerin as an index of endothelium-independent vasodilation in lung-healthy current smokers, ex-smokers, and nonsmokers. Current smokers were then treated with inhaled fluticasone for 3 wk, and all measurements were repeated after fluticasone treatment and after a subsequent 3-wk fluticasone washout period. Baseline mean Qaw and endothelium-independent Qaw reactivity were similar in the three groups. Mean endothelium-dependent Qaw reactivity was 49.5% in nonsmokers, 42.7% in ex-smokers, and 10.8% in current smokers (P < 0.05 vs. nonsmokers). In current smokers, mean baseline Qaw was unchanged after fluticasone treatment, but endothelium-dependent Qaw reactivity significantly increased to 34.9%. Qaw reactivity was again blunted after fluticasone washout. Endothelial dysfunction, as assessed by vascular reactivity, can be corrected with an inhaled corticosteroid in the airway of lung-healthy current smokers. This proof of concept can serve as the basis for future clinical investigations on the effect of glucocorticoids on endothelial function in smokers.

Exercise-related change in airway blood flow in humans: relationship to changes in cardiac output and ventilation.

This study examined the relationship between airway blood flow (Q(aw)), ventilation (V(E)) and cardiac output (Q(tot)) during exercise in healthy humans (n=12, mean age 34+/-11 yr). Q(aw) was estimated from the uptake of the soluble gas dimethyl ether while V(E) and Q(tot) were measured using open circuit spirometry. Measurements were made prior to and during exercise at 34+/-5 W (Load 1) and 68+/-10 W (Load 2) and following the cessation of exercise (recovery). Q(aw) increased in a stepwise fashion (P<0.05) from rest (52.8+/-19.5 microl min(-1) ml(-1)) to exercise at Load 1 (67.0+/-20.3 microl min(-1) ml(-1)) and Load 2 (84.0+/-22.9 microl min(-1) ml(-1)) before returning to pre-exercise levels in recovery (51.7+/-13.2 microl min(-1) ml(-1)). Q(aw) was positively correlated with both Q(tot) (r=0.58, P<0.01) and V(E) (r=0.50, P<0.01). These results demonstrate that the increase in Q(aw) is linked to an exercise related increase in both Q(tot) and V(E) and may be necessary to prevent excessive airway cooling and drying.

The effect of corticosteroids on the disposal of long-acting beta2-agonists by airway smooth muscle cells.

BACKGROUND: Organic cation transporters (OCTs) have an important role in tissue distribution and elimination of cationic drugs. Carrier-mediated disposal of cationic bronchodilators in the airway tissue, however, is incompletely understood. OBJECTIVES: We sought to assess the uptake of long-acting beta(2)-agonist bronchodilators by bronchial and vascular smooth muscle cells. METHODS: Human airway cells and tissues obtained from organ donors were evaluated for cationic drug transporter expression by means of quantitative RT-PCR and immunofluorescence. For in vitro functional studies, tritiated formoterol and tritiated salmeterol uptake by bronchial and vascular smooth muscle cells was measured. RESULTS: Quantitative RT-PCR analysis revealed high mRNA levels for the corticosteroid-sensitive OCT3 in bronchial and vascular smooth muscle cells. Immunofluorescence staining of airway sections confirmed OCT3 expression in these cells. In bronchial smooth muscle cells, uptake of the cationic formoterol was inhibited with OCT inhibitors. Corticosteroids also inhibited formoterol uptake through a rapid (within 15 minutes) nongenomic action, with the following rank order for inhibitory potency: corticosterone > budesonide > fluticasone. The corticosteroid-induced inhibition was significantly higher in vascular than bronchial smooth muscle cells. In comparison with formoterol, uptake of the noncharged lipophilic salmeterol was approximately 10-fold higher and insensitive to all OCT inhibitors and corticosteroids. CONCLUSIONS: Our findings suggest that corticosteroids, through OCT3 inhibition, rapidly interfere with the disposal of cationic drugs by smooth muscle cells in the airway. CLINICAL IMPLICATIONS: This novel immediate interaction between corticosteroids and cationic beta(2)-agonist bronchodilators supports the use of such combinations in the pharmacotherapy of asthma.

Airway and Pulmonary ß2-Adrenergic Vasodilatory Function in Current Smokers and Never Smokers.

BACKGROUND: Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of ß2-adrenoceptor-mediated vasodilation in smokers and never smokers. METHODS: In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 µg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived. RESULTS: Albuterol induced a substantial drop in mean (± SE) PVR (-67.2% ± 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (-28.6% ± 3% vs -3.1% ± 6%; P < .02). CONCLUSIONS: These results are consistent with a dysfunction in a ß2-adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium.

Airway blood flow reactivity in healthy smokers and in ex-smokers with or without COPD.

STUDY OBJECTIVES: Cigarette smoking has been associated with impaired endothelium-dependent relaxation responses in the brachial and coronary arteries (endothelial dysfunction). The aim of the present study was to determine whether the airway circulation is also affected and whether pharmacologic treatment has an effect on endothelial function in patients with COPD. METHODS AND PATIENTS: Airway blood flow (Qaw) responses to therapy with inhaled albuterol, which causes endothelium-dependent vasodilation, were measured with a noninvasive soluble-gas-uptake technique in age-matched healthy current smokers (n = 10), healthy ex-smokers (n = 10), ex-smokers with COPD (n = 10), and healthy lifetime nonsmokers. In the ex-smokers with COPD, the albuterol responsiveness measurement was repeated after 4 weeks of treatment with fluticasone/salmeterol and after a drug washout period of 4 or 8 weeks. RESULTS: The mean (+/- SE) baseline Qaw values ranged between 40.7 +/- 3.9 and 50.9 +/- 2.8 microL/min/mL anatomic dead space in the four groups (differences were not significant). The mean FEV(1) was 53.4 +/- 2.3% predicted in the ex-smokers with COPD. Albuterol inhalation increased mean Qaw significantly in lifetime nonsmokers (50.1 +/- 8.3% predicted; p < 0.05) and healthy ex-smokers (37.2 +/- 3.4% predicted; p < 0.05), but not in healthy current smokers (13.9 +/- 3.2% predicted; difference was not significant) and ex-smokers with COPD (9.7 +/- 4.5% predicted; difference was not significant). While fluticasone/salmeterol did not change Qaw significantly, it restored albuterol responsiveness (67.6 +/- 11.1% predicted; p < 0.05) in the ex-smokers with COPD; this effect was no longer seen after the drug washout period. CONCLUSIONS: Cigarette smoking is associated with a blunted vasodilator response to inhaled albuterol in the airway as an expression of endothelial dysfunction, with a partial recovery of albuterol responsiveness after smoking cessation in healthy ex-smokers but not in ex-smokers with COPD. In the latter group, combined glucocorticoid/long-acting beta(2)-adrenergic agonist treatment restores albuterol responsiveness. The role of endothelial dysfunction in the physiopathology of COPD remains to be examined.

A simplified noninvasive method to measure airway blood flow in humans.

Our laboratory has previously developed and validated a noninvasive soluble gas uptake method to measure airway blood flow (Qaw) in humans (Onorato DJ, Demirozu MC, Breitenbücher A, Atkins ND, Chediak AD, and Wanner A. Am J Respir Crit Care Med 149: 1132-1137, 1994; Scuri M, McCaskill V, Chediak AD, Abraham WM, and Wanner A. J Appl Physiol 79: 1386-1390, 1995). The method has the disadvantage of requiring eight breath-hold maneuvers for a single Qaw measurement, a complicated data analysis, and the inhalation of a potentially explosive gas mixture containing dimethylether (DME) and O2. Because of these shortcomings, the method thus far has not been used in other laboratories. We now simplified the method by having the subjects inhale 500 ml of a 10% DME-90% N2 gas mixture to fill the anatomical dead space, followed by a 5- or 15-s breath hold, and measuring the instantaneous DME and N2 concentrations and volume at the airway opening during the subsequent exhalation. From the difference in DME concentration in phase 1 of the expired N2 wash-in curve multiplied by the phase 1 dead space volume and divided by the mean DME concentration and the solubility coefficient for DME in tissue, Qaw can be calculated by using Fick's equation. We compared the new method to the validated old method in 10 healthy subjects and found mean +/- SE Qaw values of 34.6 +/- 2.3 and 34.6 +/- 2.8 microl.min(-1).ml(-1), respectively (r = 0.93; upper and lower 95% confidence limit +2.48 and -2.47). Using the new method, the mean coefficient of variation for two consecutive measurements was 4.4% (range 0-10.4%); inhalation of 1.2 mg albuterol caused a 53 +/- 14% increase in Qaw (P = 0.02) and inhalation of 2.4 mg methoxamine caused a 32 +/- 7% decrease in Qaw (P = 0.07). We conclude that the new method provides reliable values of and detects the expected changes in Qaw with vasoactive drugs. The simplicity and improved safety of the method should improve its acceptability for the noninvasive assessment of Qaw in clinical research.

Acute effect of an inhaled glucocorticosteroid on albuterol-induced bronchodilation in patients with moderately severe asthma.

BACKGROUND: We have previously shown that in patients with asthma a single dose of an inhaled glucocorticosteroid (ICS) acutely potentiates inhaled albuterol-induced airway vascular smooth muscle relaxation through a nongenomic action. An effect on airway smooth muscle was not seen, presumably because the patients had normal lung function. The purpose of the present study was to conduct a similar study in patients with asthma with airflow obstruction to determine if an ICS could acutely also potentiate albuterol-induced airway smooth muscle relaxation in them. METHODS: In 15 adult patients with asthma (mean ± SE baseline FEV1, 62% ± 3%), the response to inhaled albuterol (180 µg) was assessed by determining the change in FEV1 (ΔFEV1) for airway smooth muscle and in airway blood flow (ΔQaw) for airway vascular smooth muscle measured 15 min after drug inhalation. Using a double-blind design, the patients inhaled a single dose of the ICS mometasone (400 µg) or placebo simultaneously with or 30 min before albuterol inhalation. RESULTS: After simultaneous drug administration, mean ΔFEV1 was 0.20 ± 0.05 L (10%) after placebo and 0.32 ± 0.04 L (19%) after mometasone (P < .05); mean ΔQaw was -2% after placebo and 30% after mometasone (P < .005). When mometasone or placebo was administered 30 min before albuterol, there was a lesser and insignificant difference in ΔFEV1 between the two treatments, whereas the difference in ΔQaw remained significant. CONCLUSIONS: This pilot study showed that in adult patients with asthma with airflow obstruction, a single standard dose of an ICS can acutely increase the FEV1 response to a standard dose of inhaled albuterol administered simultaneously. The associated potentiation of albuterol-induced vasodilation in the airway was of greater magnitude and retained when the ICS was administered 30 min before albuterol. The clinical significance of this observation will have to be established by a study involving a larger patient cohort. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01210170; URL: www.clinicaltrials.gov.

Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol.

BACKGROUND: In vitro and animal experiments have shown that the transport and signaling of ß2-adrenergic agonists are pH-sensitive. Inhaled albuterol, a hydrophilic ß2-adrenergic agonist, is widely used for the treatment of obstructive airway diseases. Acute exacerbations of obstructive airway diseases can be associated with changes in ventilation leading to either respiratory acidosis or alkalosis thereby affecting albuterol responsiveness in the airway. The purpose of this study was to determine if airway pH has an effect on albuterol-induced vasodilation in the airway. METHODS: Ten healthy volunteers performed the following respiratory maneuvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation (to dissociate the effect of pH from the effect of ventilation). During these breathing maneuvers, exhaled breath condensate (EBC) pH and airway blood flow response to inhaled albuterol (ΔQ̇aw) were assessed. RESULTS: Mean ± SE EBC pH (units) and ΔQ̇aw (µl.min(-1).mL(-1)) were 6.4 ± 0.1 and 16.8 ± 1.9 during quiet breathing, 6.3 ± 0.1 and 14.5 ± 2.4 during eucapnic hyperventilation, 6.6 ± 0.2 and -0.2 ± 1.8 during hypocapnic hyperventilation (p = 0.02 and <0.01 vs. quiet breathing), and 5.9 ± 0.1 and 2.0 ± 1.5 during hypercapnic hyperventilation (p = 0.02 and <0.02 vs quiet breathing). CONCLUSIONS: Albuterol responsiveness in the airway as assessed by ΔQ̇aw is pH sensitive. The breathing maneuver associated with decreased and increased EBC pH both resulted in a decreased responsiveness independent of the level of ventilation. These findings suggest an attenuated response to hydrophilic ß2-adrenergic agonists during airway disease exacerbations associated with changes in pH. TRIAL REGISTRATION: Registered at clinicaltrials.gov: NCT01216748 .

Immediate antiinflammatory effects of inhaled budesonide in patients with asthma.

BACKGROUND: In patients with asthma, single doses of inhaled glucocorticosteroids (ICS) have been reported to have antiinflammatory actions that can be detected several hours after drug administration. However, the onset and duration of the effect have not been investigated. We therefore measured airway blood flow ([Formula: see text]aw) as an index of airway inflammation to determine the time course and dose dependence of the antiinflammatory action of an ICS in 20 patients with moderate asthma receiving regular ICS treatment. METHODS: [Formula: see text]aw and spirometry were measured before and serially for 360 minutes after a single inhaled dose of 360 µg, 720 µg, and 1,440 µg budesonide or placebo as well as after four repetitive 720-µg budesonide doses given 30 minutes apart. RESULTS: Baseline mean [Formula: see text]aw was increased and FEV1 was decreased without significant differences among the 5 treatment days. After budesonide inhalation, there was a transient, dose-dependent decrease in mean [Formula: see text]aw from 12 to 21%, with significant differences from baseline at 60 and 90 minutes for the 720-µg and 1,440-µg doses (P < 0.05). Thirty minutes after four repetitive budesonide administrations, mean [Formula: see text]aw was 28% below baseline (P < 0.05) and remained 11% below baseline after 270 minutes. There was no change in mean FEV1 after any of the treatments. CONCLUSIONS: In subjects with moderate asthma who use ICS regularly, inhaled budesonide caused a transient dose-dependent vasoconstriction in the airway, thereby reversing one manifestation of airway inflammation. These results suggest that a pure controller medication can have immediate beneficial effects not paralleled by changes in airflow. Clinical trial registered with www.clinicaltrials.gov (NCT 01219738).

Airway vascular endothelial function in healthy smokers without systemic endothelial dysfunction.

BACKGROUND: Cigarette smoking can lead to systemic endothelial dysfunction. Since the airway circulation is exposed to a high concentration of cigarette smoke constituents, we reasoned that airway vascular endothelial dysfunction could be present in healthy smokers without systemic endothelial dysfunction. OBJECTIVES: The purpose of this study was to compare airway and systemic endothelial function and measure markers of systemic inflammation in lung-healthy current smokers. Since endothelial dysfunction in smokers has been related to systemic inflammation, we also investigated its response to an inhaled glucocorticosteroid (ICS). METHODS: Fifteen healthy, current smokers and 17 healthy, lifetime nonsmokers were enrolled. Smokers were randomly assigned to 3-week treatments with inhaled fluticasone propionate or placebo in a crossover design. Vascular endothelial function was assessed in the airway by the airway blood-flow response to inhaled albuterol (ΔQaw) and in the extrapulmonary circulation by brachial arterial flow-mediated vasodilation (FMD). Venous blood was collected for C-reactive protein and IL-6. RESULTS: Baseline parameters did not differ between groups except for ΔQaw, which was greater in nonsmokers (45% ± 12%) than smokers (1% ± 12%) (P = .001). In the smokers, ICS treatment increased Qaw to 41% ± 7% (P < .001), but had no effect on FMD or inflammatory markers. There was an inverse relationship between baseline and ICS-induced changes in ΔQaw. CONCLUSIONS: Healthy smokers with no signs of systemic inflammation or endothelial dysfunction display impaired airway vascular endothelial function, possibly preceding systemic endothelial dysfunction. Airway endothelial function was restored with an ICS, and the response was directly related to the severity of endothelial dysfunction.

Acute effects of salmeterol and fluticasone propionate alone and in combination on airway blood flow in patients with asthma.

BACKGROUND: The airway contains airway smooth muscle and airway vascular smooth muscle. The acute effects of inhaled long-acting ß(2)-adrenergic agonists (LABAs) alone, or in combination with an inhaled glucocorticoid (ICS), on airway smooth muscle tone in asthma are known; however, to the best of our knowledge, their effect on airway vascular smooth muscle tone has not been investigated previously. The objective of this study was to investigate the immediate effects of a LABA and an ICS alone and in combination on airway blood flow (Qaw) as an index of airway vascular smooth muscle tone in patients with stable asthma. METHODS: Fourteen subjects with moderate asthma inhaled single doses of salmeterol (50 µg), fluticasone propionate (250 µg), salmeterol/fluticasone propionate (50/250 µg), or placebo; Qaw was measured before and serially for 240 min after drug administration. RESULTS: Mean Qaw increased after salmeterol and salmeterol/fluticasone propionate, with peaks at 60 min of 34% and 40%, respectively, and returned to baseline by 240 min after inhalation. Fluticasone propionate alone caused a transient decrease in mean Qaw. The maximal changes in Qaw, which occurred at different times, were 60% for salmeterol, 67% for salmeterol/fluticasone propionate, and -19% for fluticasone propionate (P < .05 vs placebo for all). CONCLUSIONS: The LABA salmeterol has an acute vasodilator action on the airway of subjects with stable asthma. The addition of fluticasone propionate, which by itself causes vasoconstriction, does not attenuate the salmeterol-induced vasodilation, suggesting that fluticasone propionate potentiates the vasodilator effect of salmeterol. The vasodilation could be of clinical benefit by promoting the vascular clearance of inflammatory mediators including spasmogens from the airway. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01231230; URL: www.clinicaltrials.gov.

Effect of montelukast and fluticasone propionate on airway mucosal blood flow in asthma.

Asthma is associated with an increase in airway blood flow (Qaw), presumably as a manifestation of airway inflammation. We therefore determined the effect of the antiinflammatory agents montelukast (ML) and fluticasone propionate (FP) on Qaw in 12 patients with mild intermittent asthma. Using a double-blind approach, Qaw along with FEV(1) and Vmax(50) were determined before and after a 2-week treatment period with either ML (10 mg/day), FP (440 microg/day), or 10 mg of ML plus 440 microg of FP daily, separated by 2-week washout periods. Mean (+/- SEM) Qaw ranged from 68 +/- 4.2 to 71.8 +/- 5.9 microl x minute(-1) x ml(-1) anatomic dead space before the treatment periods. ML, FP, and ML plus FP decreased mean Qaw by 21.5, 20.8, and 26.9%, respectively (p < 0.05 for all). No significant difference was observed among the three regimens. FEV(1) and Vmax(50) were not changed by any of the treatments. We conclude that at the dosages used, ML and FP are equipotent in reducing Qaw in patients with mild asthma, and that the magnitude of the response is not greater if the two drugs are combined. The results also suggest that the vascular effects of these agents can be assessed independent of their effects on airway function.

Nongenomic actions of glucocorticosteroids on the airway vasculature in asthma.

Inhaled glucocorticosteroids (corticosteroids) continue to be the standard treatment for nonexacerbated asthma because of their anti-inflammatory actions. These include effects on the airway vasculature, which participates in the inflammatory process. Corticosteroids are now known to have genomic as well as nongenomic effects that involve different mechanisms of action. The genomic vascular effects of inhaled corticosteroids include a decrease in airway wall hypervascularity (inhibition of angiogenesis), reversal of the increased airway blood flow, and inhibition of vascular hyperpermeability and leukocyte recruitment. In addition, inhaled corticosteroids decrease airway blood flow acutely (within minutes) and reversibly through a nongenomic action that involves noradrenergic neurotransmission. This effect is likely related to the binding of inhaled corticosteroids to the plasma membrane of and the inhibition of the extraneuronal monoamine transporter on airway vascular smooth muscle cells, thereby increasing norepinephrine concentrations at alpha(1)-adrenoceptors and causing airway vascular smooth muscle contraction and a decrease in airway blood flow. Inasmuch as vascular hyperperfusion is a manifestation of airway inflammation, the acute vasoconstriction could also be considered an anti-inflammatory effect of inhaled corticosteroids.