Effects of smoking cessation on lung function and airway inflammation in smokers with asthma

RATIONALE: Active smoking in asthma is associated with worsening of symptoms, accelerated decline in lung function, and impaired response to corticosteroids. OBJECTIVES: To examine the short-term effects of smoking cessation on lung function, airway inflammation, and corticosteroid responsiveness in smokers with asthma. METHODS AND MEASUREMENTS: Smokers with asthma were given the option to quit or continue smoking. Both groups underwent spirometry and induced sputum at baseline and at 1, 3, and 6 wk. Cutaneous vasoconstrictor response to topical beclometasone, airway response to oral prednisolone, and sensitivity of peripheral blood lymphocytes to corticosteroids were measured before smoking cessation and at 6 wk. MAIN RESULTS: Of 32 subjects recruited, 11 opted to continue smoking (smoking control group). Of 21 subjects who opted for smoking cessation, 10 quit smoking for 6 wk (quit group). In the comparison of quitters with smokers at 6 wk, the mean (confidence interval [CI]) difference in FEV(1) was 407 ml (21, 793), p = 0.040, and the proportion of sputum neutrophils was reduced by 29 (51, 8), p = 0.039. Total cutaneous vasoconstrictor response score to topical beclometasone improved after smoking cessation with a mean (CI) difference of 3.56 (0.84, 6.28), p = 0.042, between quitters and smokers. There was no change in airway corticosteroid responses after smoking cessation. CONCLUSIONS: By 6 wk after smoking cessation, subjects who quit smoking had achieved considerable improvement in lung function and a fall in sputum neutrophil count compared with subjects who continued to smoke. These findings highlight the importance of smoking cessation in asthma.     

Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers.

Interleukin (IL)-10 is a potent regulatory cytokine that decreases inflammatory responses. This study investigated whether IL-10 levels in the airway are decreased in chronic airway inflammation associated with asthma or chronic obstructive pulmonary disease (COPD). Sputum was obtained from 12 healthy nonsmokers, 10 healthy smokers, 16 asthmatic patients and seven patients with COPD by means of the sputum-induction method. The IL-10 level was measured via enzyme-linked immunosorbent assay and immunocytochemical analysis. The IL-10 level in sputum was significantly lower in asthma and COPD patients and healthy smokers compared with that in healthy nonsmokers (nonsmokers, 68.0+/-11.3; smokers, 45.3+/-7.8; asthma, 26.7+/-4.0; COPD, 18.0+/-2.3 pg x mL(-1); p<0.05 for nonsmokers versus the other groups). The percentage of IL-10-positive cells in the sputum was also significantly lower in asthma and COPD and in smokers (nonsmokers, 13.2+/-1.7; smokers, 6.4+/-1.8; asthma, 5.4+/-3.5; COPD, 3.5+/-1.6%; p<0.05 for nonsmokers versus the other groups). The IL-10-positive cell appeared morphologically to be the macrophage. These data suggest that the reduced level of interleukin-10 within the airways plays a role in the pathogenesis of chronic airway inflammation in asthma and chronic obstructive pulmonary disease.     

Systemic CD4+ T-cell activation is correlated with FEV1 in smokers

The inflammation of the lungs in chronic obstructive pulmonary disease (COPD) is characterised by increased numbers of macrophages, neutrophils and T-cells. Decline in lung function in these patients has been correlated to the number of CD8+ T-cells present in the lung as well as to a decline in the ratio of CD4+/CD8+ T-cells. Although systemic components are likely to be present, circulating lymphocyte populations in COPD patients have not been well characterised. This study aimed at correlating lung function to expression of five different T-cell activation markers on peripheral blood CD4+ and CD8+ T-cells in COPD patients and matched smokers. Furthermore, proportions of lymphocyte populations and degree of systemic T-cell activation in COPD patients were compared to that in smokers and never-smokers. Peripheral blood lymphocytes from six never-smokers, eight smokers and 17 smokers with COPD were analysed using flowcytometry. The number of lymphocytes per millilitre was higher in smokers than in never-smokers. No differences were found between the three groups in regard to proportions of lymphocyte populations, but the number of CD4+ T-cells in smokers was higher than in both never-smokers and COPD patients. The degree of T-cell activation was similar in all patient groups; however, a clear correlation between CD69 expression on CD4+ T-cells and lung function (FEV(1)% of predicted) was found when examining current smokers, with or without COPD. Elevated numbers of CD69+ CD4+ T-cells in blood thus seem to be protective against airway obstruction in smokers while still exposed to cigarette smoke, the main inducer of COPD.     

Cigarette smoking alters bronchial mucosal immunity in asthma

RATIONALE: Cigarette smoking worsens asthma and is associated with reduced response to corticosteroid therapy. As cigarette smoke is known to have immunomodulatory effects, we hypothesized that one mechanism by which smoking mediates its adverse effect is by reduction of the numbers of bronchial mucosal dendritic cells (DCs), which control B-cell growth and T-cell responses. OBJECTIVES: We set out to sample the bronchial mucosa in smoking and never-smoking patients with asthma and to count DCs, B cells, and cells expressing genes for two key T-lymphocyte regulatory cytokines. METHODS: Twenty-one never-smoker patients with asthma (6 steroid naive), 24 smoker patients with asthma (9 steroid naive), and 10 healthy never-smokers (control subjects) were recruited and their endobronchial biopsy samples were immunostained for detection of mature DCs (CD83(+)), Langerhans cells (CD1a(+)), B lymphocytes (CD20(+)), and helper T-cell type 1 (IFN-gamma) and helper T-cell type 2 (IL-4) cytokine-expressing cells. MEASUREMENTS AND MAIN RESULTS: The number (per square millimeter) of CD83(+) mature DCs was significantly lower in smoker patients with asthma (median [range]: 37 [0, 131]) in comparison with never-smoker steroid-naive and steroid-treated patients with asthma (76 [24, 464]; p = 0.006) or control subjects (85 [40, 294]; p = 0.004). Moreover, B cells were fewer in smoker (26 [4, 234]) versus never-smoker steroid-naive and steroid-treated patients with asthma (45 [10, 447]; p = 0.01) and in smoker steroid-naive patients with asthma (23 [4, 111]) versus control subjects (34 [10, 130]; p = 0.05). The number of cells expressing IFN-gamma showed a trend toward fewer in smoker (70 [6, 24]) versus never-smoker steroid-naive patients with asthma (144 [44, 323]; p = 0.10). CONCLUSIONS: There are important and statistically significant differences in the number of CD83(+) mature DCs and B cells in the large airways of smokers with asthma. We speculate that their reductions may render patients with asthma less responsive to corticosteroids and more susceptible to infection.     

The expression of lymphocyte surface antigens in bronchial biopsies, bronchoalveolar lavage cells and blood cells in healthy smoking and never-smoking men, 60 years old

In this study we investigated if smoking subjects with a normal or slightly decreased lung function differ in the lymphocyte pattern compared to never-smokers. In a group of 'healthy' smokers (n = 58) and never-smokers (n = 34) 60 years old, we investigated the lymphocyte pattern in both BAL (n = 30 and n = 18 respectively), bronchial epithelium and lamina propria (n = 14 and n = 10 respectively) and blood. We found that all subjects, despite smoking history, had a higher number of CD8+ cells per mm2 in the epithelium compared to the lamina propria in the bronchial biopsies. In smokers, these CD8+ cells were significantly negatively correlated to FEV1 (r = -0.56, P = 0.04). In smokers, the number of CD8+ lymphocytes was higher and the T cell activation markers (CD57+ and CD28+) were lower in BAL, than in never-smokers. This last finding was also seen in blood for CD3+ 57+. We conclude, that in 'healthy' smokers the lymphocyte patterns are different compared to never-smokers, to some extent in BAL. There is also a relation between lymphocytes in the bronchial mucosa and lung function. This has previously been shown in patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis but not in asymptomatic smokers.     

Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma

The study was designed to assess the effect of cigarette smoking on the therapeutic response to oral corticosteroids in chronic stable asthma. We performed a randomized, placebo-controlled, crossover study with prednisolone (40 mg daily) or placebo for 2 weeks in smokers with asthma, ex-smokers with asthma, and never-smokers with asthma. All subjects had reversibility in FEV1 after nebulized albuterol of 15% or more and a mean postbronchodilator FEV1% predicted of more than 80%. Efficacy was assessed using FEV1, daily PEF, and an asthma control score. There was a significant improvement after oral prednisolone compared with placebo in FEV1, ml (mean difference, 237; 95% confidence intervals, 43, 231; p = 0.019), morning PEF L/m (mean difference, 36.8; 95% confidence intervals (CI), 11, 62; p = 0.006), and asthma control score (mean difference, -0.72; 95% CI, -1.2, -0.3; p = 0.004) in never-smokers with asthma but no change in smokers with asthma (mean differences of 47, 6.5, and -0.05 with p values of 0.605, 0.47, and 0.865, respectively). Ex-smokers with asthma had a significant improvement in morning and night PEF (mean difference, 29.1; CI, 2.3, 56; p = 0.04 and 52.4; CI, 26, 79; p = 0.003, respectively), but not in FEV1 or asthma control score. We conclude that active smoking impairs the efficacy of short-term oral corticosteroid treatment in chronic asthma.     

Monocyte-induced inhibition of lymphocyte response to phytohaemagglutinin in progressive systemic sclerosis.

In patients with progressive systemic sclerosis (PSS) lymphocyte responses to phytohaemagglutinin (PHA) are abnormal (27.2 +/- 3.5 X 10(-3) counts per minute (cpm) versus 69.8 +/- 4.4 X 10(-3) for normal persons, p less than 0.005). Removal of adherent peripheral blood mononuclear cells improves the response of PSS lymphocytes (42.3 +/- 3.4 X 10(-3) cpm, 155% of control) but diminishes the response of normal lymphocytes (60.3 +/- 5.9 +/- 10(-3), 86% of control). Supernatant fluids from cultures of PSS unfractionated and adherent cells depress normal T cell response to PHA (64% and 55% of control respectively), but supernatant fluids from normal unfractionated and adherent cells do not (104% and 101% of control). Supernatant fluids of PSS and normal adherent cells, cultured in the presence of indomethacin, are not inhibitory to normal T cells (109 +/- 15% and 124 +/- 14% of control respectively). Supernatant fluids from PSS patients are more inhibitory than comparable fluids from patients with systemic lupus erythematosus (60 +/- 8% of control versus 80 +/- 5% of control). These data support the hypothesis that cellular immunity is abnormal in patients with PSS and indicate that adherent mononuclear cells mediate at least one component of the abnormality via an indomethacin-sensitive mechanism.     

Differential flow analysis of exhaled nitric oxide in patients with asthma of differing severity

BACKGROUND: The majority of asthmatic patients achieve control of their illness; others do not. It is therefore crucial to validate/develop strategies that help the clinician monitor the disease, improving the response to treatment. METHODS: We have quantified the inflammation in central and peripheral airways by measuring exhaled nitric oxide (NO) at multiple exhalation flows in 56 asthmatics at different levels of severity (mild, n = 10; moderate stable, n = 17; moderate during exacerbation, n = 11; severe, n = 18, 7 of whom were receiving oral corticosteroids) and 18 healthy control subjects. The reproducibility of the measurement was also assessed. RESULTS: Bronchial NO (Jno) in patients with mild asthma (2,363 +/- 330 pL/s) [mean +/- SD] was higher than in patients with moderate stable asthma (1,300 +/- 59 pL/s, p < 0.0005), in patients with severe asthma receiving inhaled corticosteroids (ICS) [1,015 +/- 67 pL/s, p < 0.0005], and healthy control subjects (721 +/- 22 pL/s, p < 0.0001). There were no differences between Jno in patients with mild asthma compared to patients with severe asthma receiving ICS and oral corticosteroids (2,225 +/- 246 pL/s). Patients with exacerbations showed a higher Jno (3,475 +/- 368.9 pL/s, p < 0.05) compared to the other groups. Alveolar NO was higher in patients with severe asthma receiving oral corticosteroids (3.0 +/- 0.1 parts per billion [ppb], p < 0.0001) than in the other groups but was not significantly higher than in patients with moderate asthma during exacerbation (2.8 +/- 0.3 ppb). No differences were seen in NO diffusion levels between the different asthma groups. All the measurements were highly reproducible and free of day-to-day and diurnal variations. CONCLUSIONS: Differential flow analysis of exhaled NO provides additional information about the site of inflammation in asthma and may be useful in assessing the response of peripheral inflammation to therapy.     

Stimulation of lymphocytes from rheumatoid arthritis patients by mitogens and IgG.

In the first part of this work patients with rheumatoid arthritis (RA), 36 cases and normal subjects, 49 cases have been studied by lymphocyte cultures stimulated by phytohaemagglutinin (PHA), Concanavalin A (Con A), pokeweed mitogen (PWM) and Con A convalently bound to sepharose 4 B (Con A-S). The comparisons between the two groups have shown a significant difference between the RA lymphocytes and the control lymphocytes stimulated by PHA and Con A. However no statistical difference has been found between the two lymphocytes populations stimulated by PWM and Con A-S. In view to determining the lymphocyte population stimulated by each mitogen, separations of B- and T-cells from peripheral blood have been performed according to the ability for the T-cells population to bind the sheep red blood-cells (rosette forming cells). The T-cell rich population was only stimulated by PHA, Con A and PWM. Although the T-cell depleted one has shown no response to these mitogens, a response to Con A-S was elicited. In the second part of this work, patients with RA, patients with positive tuberculin (PPD) skin-tests and controls were studied. The lymphocytes from these groups were cultured in serum-free medium to obtain cell-free supernatants. These lymphocyte cultures were preincubated with the appropriate antigen or reconstituted after removal of the cells. Supernants from RA lymphocytes stimulated in vitro by undenaturated IgG induced an inhibition of the leucocyte migration, as well as the supernatants from tuberculin-sensitized lymphocytes. However, supernatants from non-RA lymphocytes or tuberculin-unsensitized lymphocytes did not show such an inhibition. These MIF like supernatants have been studied by Sephadex G-100 gel filtration. A MIF like activity has been found for PPD and IgG supernatants between the chymotrypsinogen (MW 23,000) and the lysozyme (MW 17,000). This MIF like activity could be due to RA lymphocytes stimulated by undenatured IgG.     

Timing of prednisone and alterations of airways inflammation in nocturnal asthma.

Asthmatic subjects prone to nocturnal worsening demonstrate overnight recruitment of inflammatory cells into the airways. The influence of dose timing on the ability of corticosteroids to block circadian recruitment of inflammatory cells into asthmatic airways and attenuate the nocturnal worsening of asthma is unclear. In a double-blind, placebo-controlled, crossover design, we evaluated the response of seven asthmatic subjects with respect to overnight spirometry, blood eosinophil counts, and bronchoalveolar lavage cytology to a single variably timed 50 mg oral dose of prednisone given at 0800, 1500, or 2000 h. Compared to placebo, a single prednisone dose at 1500 h resulted in a reduction in the overnight percentage fall in FEV1 (-28.2 +/- 7.3 versus -10.4 +/- 4.5%, p = 0.04) and improvement in the 0400 h FEV1 (2.53 +/- 0.38 versus 3.43 +/- 0.38 L, p = 0.03). In contrast, neither a 0800 nor 2000 h prednisone dose compared to placebo resulted in overnight spirometric improvement. Also following the 1500 h prednisone dose, blood eosinophil counts were significantly reduced at both 2000 and 0400 h. Lastly, the 1500 h dosing resulted in a pan-cellular reduction in bronchoalveolar lavage cytology (p < or = to 0.05 for all cell lines compared to placebo), but neither alternative dose schedule significantly reduced any cell line. Our data support the relevance of timing of prednisone dose in altering the inflammatory milieu and spirometric decline associated with nocturnal worsening of asthma.     

Cough and phlegm are important predictors of health status in smokers without COPD

STUDY OBJECTIVES: The health-related quality of life of smokers without COPD and that of ex-smokers has not been defined. If abnormal, the role of small airways disease and that of cough and phlegm have never been evaluated. Therefore, the aim of the study was to explore whether the differences in quality of life between smokers and ex-smokers could be explained by cough and phlegm, differences in pulmonary function tests, or exercise capacity. DESIGN: Observational, prospective. SETTING: Pulmonary and Critical Care Division, COPD Center at St. Elizabeth's Medical Center. POPULATION: In 36 smokers, 21 ex-smokers (stopped smoking for > 20 years), 19 never-smokers with normal FVC and FEV(1) values, and 41 patients with COPD (FEV(1) 38 +/- 11% predicted [mean +/- SD]), the St. George's Respiratory Questionnaire (SGRQ), pulmonary function tests, and a 6-min walk distance (6MWD) were performed. RESULTS: The total SGRQ scores were worse in current smokers (15 +/- 15) than in ex-smokers (6 +/- 4) or never-smokers (4 +/- 3) [p < 0.05]. As expected, the worst score was seen in COPD (50 +/- 15). After correcting for cough and phlegm, the difference in SGRQ scores between smokers and ex-smokers disappeared. In current and ex-smokers, the SGRQ score was associated with the exposure to pack-years smoking history (r = 0.45, p < 0.01, and r = 0.83, p < 0.0001, respectively) but independent of lung function or exercise parameters (6MWD). CONCLUSIONS: In smokers without COPD, the abnormal SGRQ score is due to the noxious effect of cigarette smoke, resulting in cough and phlegm, independent of its physiologic effects.     

吸烟对支气管哮喘患者吸入糖皮质激素疗效的影响：荟萃分析

目的：荟萃分析吸烟对支气管哮喘(简称哮喘)患者吸入糖皮质激素治疗效果的影响。方法检索 PubMed 数据库、Embase 数据库、Cochrane 图书馆临床对照试验数据库、中国知网全文数据库、万方科技期刊全文数据库。纳入2014年10月以前对有吸烟史的哮喘患者进行吸入糖皮质激素治疗的研究。运用 Cochrane 荟萃分析的方法,由2名评价员独立对试验进行筛选、质量评价、数据提取和交叉核对。使用 Stata 9和 Review Man 5.3软件对数据合并进行统计分析。结果共14篇文献纳入本研究,包括4667例哮喘患者,接受同等剂量吸入糖皮质激素治疗后,吸烟组哮喘患者 FEV1改善值低于非吸烟组哮喘患者[均数差(SMD)为-0.28 L;95%可信区间(95% CI )为(-0.46~-0.10),P <0.05];最大呼气流速改善程度也低于非吸烟组[SMD 为-0.58,95% CI 为(-1.01~-0.14),P <0.01]。结论吸烟与哮喘患者吸入糖皮质激素疗效下降有关。     

Endothelial interactions of neutrophils under flow in chronic obstructive pulmonary disease.

It is generally accepted that the neutrophil is central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Enhanced endothelial interactions of this cell may contribute to the susceptibility of smokers who develop the disease; however, these interactions have not previously been studied in COPD. The aim of the current study was to determine whether enhanced endothelial interactions of neutrophils from smokers are a predisposing factor for the development of COPD. Endothelial interactions under flow and adhesion molecule expression of peripheral blood neutrophils were compared between seven never-smokers (NS), seven healthy smokers (HS), 11 COPD patients with severe alpha1-antitrypsin deficiency (PiZ) and neutrophils from 11 COPD patients without the deficiency (PiM). Total adhesive and migratory responses (per mm2 endothelium per 10(6) neutrophils) were significantly greater in the PiM group (mean+/-se 704.2+/-57.9 versus 509.3+/-48.8 in the PiZ group, 499.3+/-40.1 in the HS and 491.2+/-33.7 in the NS). This corresponded with increased macrophage antigen-1 (CD11b) expression on stimulated neutrophils in the PiM group compared with the PiZ group (mean+/-se relative fluorescence intensity 1.4+/-0.1 versus 1.1+/-0.1). In conclusion, the enhanced endothelial interaction of neutrophils from smokers who have developed chronic obstructive pulmonary disease in the presence of normal levels of alpha1-antitrypsin deficiency, but not in those with severe alpha(1)-antitrypsin deficiency, suggests that this is a predisposing factor for the development of the disease, and upregulation of macrophage antigen-1 may be responsible.     

Beta-blocker action on lymphocyte proliferative response in essential hypertension

The proliferative response of phytohaemagglutinin (PHA) - stimulated lymphocytes of healthy donors and hypertensive subjects was analysed according to 3H-thymidine incorporation and cell cycle phase position on a flow cytofluorimeter. 3H-thymidine uptake and the percentage of cells in (S + G2) phase were significantly lower in hypertensive patients. After short-term propranolol administration the lymphocyte blastogenic response in essential hypertension increased by 30--100%. The data suggest that the change in mitogenic response of lymphocytes in essential hypertension results from changes in the distribution of lymphocyte subclasses. The connection between the sympathoadrenal and immune system is discussed.     

Beta-adrenergic receptors of lymphocytes in children with allergic respiratory diseases

The beta-adrenergic receptor binding sites on peripheral lymphocytes in children with bronchial asthma (n = 16) and seasonal allergic rhinitis (n = 8) were examined in comparison with normal controls (n = 18) by means of 124I-cyanopindolol. The number of beta-adrenergic receptors was significantly lower in the asthmatic group (858 +/- 460/lymphocyte) than in the controls (1564 +/- 983/lymphocyte). The value (1891 +/- 1502/lymphocyte in children with allergic rhinitis was slightly higher than that in healthy controls. Of the 24 patients suffering from allergic diseases of the lower or upper airways, the bronchial histamine provocation test was performed in 21; 16 gave positive results, while 5 were negative. No difference in beta-adrenergic receptor count was found between the histamine-positive and negative patients. Neither was there any correlation between the number of beta-adrenergic receptors and the high (16/24) and low (8/24) serum IgE concentrations found in allergic patients. The significant decrease in beta-adrenergic receptor count in asthmatic children lends support to Szentiványi's concept. Further qualitative and quantitative analysis of lymphocyte beta-adrenergic receptors may provide an individual approach to the treatment of bronchial asthma with beta-sympathomimetic drugs.     

Decreased lymphocyte reactivity to a suboptimal concentration of phytohemagglutinin in Sj?gren's syndrome.

Significantly decreased lymphocyte reactivity to a suboptimal concentration of phytohemagglutinin (PHA) was found in patients with Sj?gren's syndrome (SS), whereas the response to an optimal concentration was generally normal. Kinetic studies were performed on control lymphocytes. Only suboptimal PHA concentrations stimulated tritiated thymidine (3H-TdR) incorporation in proportion to the number of potentially reactive lymphocytes. Kinetic studies of SS patients suggested that their low reactivity was attributable to fewer functionally reactive lymphocytes rather than to a decreased rate of proliferation.     

EFFECT OF BECLOMETHASONE DIPROPIONATE DELIVERED BY AEROSOL IN PATIENTS WITH ASTHMA

Beclomethasone dipropionate has been inhaled from a pressurised aerosol by seventeen patients with asthma and has provided the only form of corticosteroid treatment in these patients for 2 to 6 months. Nine patients were not taking systemic corticosteroids when the steroid aerosol treatment was started, and eight others were transferred from prednisolone to the new treatment. The steroid aerosol seemed to exert a significant topical corticosteroid action on the airways and provided the expected clinical benefits of corticosteroids seen in many patients with asthma. The therapeutic results were confirmed by measurements of forced expired volume in one second. Basal plasma-hydrocortisone levels did not become low in any patient, and in those transferred from prednisolone the plasma-hydrocortisone rose to normal. This apparent return of adrenal responsiveness was confirmed by measuring the response to tetracosactrin stimulation in eight patients. The results support the idea that inhaled beclomethasone dipropionate acts in a similar way to systemic corticosteroids in patients with asthma but seems to have less systemic effect. Systemic corticosteroids had to be given on occasion to six patients over the period of study, and this indicates the need to compare the therapeutic potency of the steroid aerosol with systemic corticosteroids to confirm that beclomethasone-dipropionate aerosol treatment does have a significant topical action.     

Cutaneous delayed-type hypersensitivity reactions in smokers with chronic bronchitis and recurrent exacerbations: comparison with asymptomatic smokers and never-smokers.

The aim of the present study was to investigate whether smoking patients with chronic bronchitis (CB) and recurrent exacerbations show signs of depressed cell-mediated immunity (CMI), as reflected in the cutaneous delayed-type hypersensitivity (DTH) reaction, in comparison with asymptomatic smokers and healthy never-smokers. The study was a comparative clinical study performed at a university hospital center of respiratory medicine. Sixteen smokers with stable CB and recurrent exacerbations, five of whom had mild airflow obstruction, 18 asymptomatic smokers and 18 healthy never-smokers, all aged between 35 and 64 years, participated. No subjects treated with corticosteroids or N-acetylcysteine were included. Cutaneous DTH-reactions to seven recall antigens were assessed with Multitest, a standardized in vivo test of clinical CMI. Reactions were assessed 48 h after application by measurement of skin induration. A score (sum in mm of positive reactions) was created to assess overall reactivity. Neither the score nor the number of positive reactions differed significantly between the three study groups. Men had a significantly higher reactivity than women (P < 0.05) irrespective of group affiliation. No influence of smoking status on DTH reactivity could be seen. In the CB group no correlation was found between DTH reactivity and number of exacerbations the past 2 years. Patients with chronic bronchitis and recurrent exacerbations did not differ from asymptomatic smokers or healthy never-smokers with respect to cutaneous DTH reactions. Depression of CMI, as measured in this study, does not seem to be a primary factor behind recurrent exacerbations in smokers with CB.     

Enhancement of human T lymphocyte colony formation by 12-O-tetradecanoylphorbol-13-acetate (TPA)

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on human T lymphocyte lymphocyte colony formation in vitro were investigated. The number of T lymphocyte colonies was increased 4-5 times over that of controls by the addition of TPA (10(-7) - 10(-9) M) to phytohemagglutinin (PHA)-containing cultures. Few colonies were observed when stimulated with TPA in the absence of PHA. In the cultures containing a sufficient amount of exogenous T cell growth factor (TCGF), the enhancement of T lymphocyte colony formation by TPA was not observed. TPA enhanced TCGF production by peripheral lymphocytes stimulated with PHA. The optimal concentrations of TPA for T lymphocyte colony formation were similar to those for TCGF production. These findings suggest that TPA enhanced T lymphocyte colony formation by stimulating endogenous TCGF production. Interestingly, T lymphocyte colony formation was not inhibited even at high concentrations of TPA that usually inhibit myeloid and erythroid colony formation. This difference may be due to different sensitivities to TPA between T lymphocyte colony-forming cells and myeloid and erythroid colony-forming cells.     

Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma.

There are few data regarding the potential effects of antiasthma treatment on indices of airway remodeling, such as the increased subepithelial airway vascularity in patients with asthma. We studied 45 symptomatic subjects with asthma who were receiving treatment with low dose inhaled corticosteroids (ICS) (range 200-500 microg twice a day) and 28 normal subjects without asthma as a control population. Subjects underwent bronchoscopy with airway biopsy and subjects with asthma were then randomized to receive supplementary inhaled salmeterol 50 microg twice a day, fluticasone propionate 100 microg twice a day, or placebo for 3 mo in addition to their baseline ICS. Biopsy of the airway was then repeated. The biopsies were analyzed for vascular structures in the subepithelial lamina propria. Sufficient biopsy material was available for analysis of vascularity in 34 of the subjects with asthma and 28 of the normal subjects. We confirmed that airways of subjects with asthma had a significant increase in the number of vessels/mm2 of lamina propria compared with airways of normal subjects (524 +/- 137 vessels/mm2, n = 34 versus 425 +/- 130 vessels/mm2, n = 28; p = 0.004). There was a decrease in the density of vessels of lamina propria after treatment only in the salmeterol group compared with baseline (before, 535 +/- 153 vessels/mm2 versus after, 400 +/- 142 vessels/mm2; n = 12; p = 0.04). There was no significant change within the fluticasone (n = 11) or placebo (n = 11) treatment groups, but also no significant differences between the groups. Notably, no treatment was associated with increased airway wall vascularity. The demonstrated fall in vessel number within the salmeterol-treated group may suggest an advantageous effect of long-acting beta2-agonists on this manifestation of airway remodeling over the 3-mo time scale of this study, which is complementary to the action of ICS on airway vascularity.