Ultrastructural heterogeneity of the alveolar macrophages from tobacco smokers with chronic bronchitis.

Alveolar macrophages recovered by bronchoalveolar lavage from 14 heavy smokers with chronic bronchitis were assessed. Ultrastructural examination revealed marked cellular heterogeneity. Three subpopulations of alveolar macrophages were readily identifiable. These have been termed "young," "mature," and "degrading," reflecting their ultrastructural features. In addition, a majority of the cells were found to be positive by TUNEL staining, indicating DNA damage, but a very small percentage tested positive for Caspase-3, suggesting that apoptosis might not account for the DNA damage in at least some of these cells. A small percentage of proliferating cells were noted.

Smoking cessation.

Cessation of cigarette smoking is the single most important therapeutic intervention that is effective in reducing the symptoms of COPD and in preventing its onset. Smoking cessation is, therefore, a major goal in efforts to mitigate the burden of this disease. This review will consider the pharmacologic and behavioral therapies that have been used to assist smokers in overcoming their addiction. These strategies assist a significant minority of smokers to stop smoking and, thus, they can have an important positive impact on COPD as well as on other health outcomes.

Modulation of elastase binding to elastin by human alveolar macrophage-derived lipids.

Human neutrophil elastase (HNE), an enzyme secreted by activated neutrophils, can bind to and degrade extracellular matrix including human lung elastin. This protease is believed to play an important role in several destructive processes including pulmonary emphysema. In this study, we hypothesized that an alveolar macrophage (AM) product or products may interact with neutrophil elastase (NE) and modulate its binding to elastin. Elastase binding to elastase was evaluated by a modified elastase functional assay using a synthetic substrate. Supernatants from cultured AM inhibited elastase binding to elastin at a dose-dependent manner without inhibiting functional elastase activity. The AM products had a heterogeneous molecular weight ranging from 440,000 to 54,000. The activity was heat-stable, but was lost after ultracentrifugation. After lipid fractionation, neither the aqueous nor the lipid fractions contained activity, suggesting that the factor may be a lipid complex. Culture supernatants from smokers' AM released significantly higher amounts of the factor than nonsmokers. In addition, high-molecular-weight elastase was present in bronchoalveolar lavage fluid (BALF) obtained from patients with pneumonia. Most of the in vivo high-molecular-weight elastase was lost after lipid extraction. In conclusion, macrophages release a factor or factors, probably lipid, which can interact with NE and inhibit its binding to human lung elastin without inhibiting elastase activity. This macrophage-derived factor may play a role in protecting the lung from NE by partitioning elastase into the airspace and thus protecting the interstitial connective tissue matrix from elastase degradation.

A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.

BACKGROUND AND METHODS: Use of nicotine-replacement therapies and the antidepressant bupropion helps people stop smoking. We conducted a double-blind, placebo-controlled comparison of sustained-release bupropion (244 subjects), a nicotine patch (244 subjects), bupropion and a nicotine patch (245 subjects), and placebo (160 subjects) for smoking cessation. Smokers with clinical depression were excluded. Treatment consisted of nine weeks of bupropion (150 mg a day for the first three days, and then 150 mg twice daily) or placebo, as well as eight weeks of nicotine-patch therapy (21 mg per day during weeks 2 through 7, 14 mg per day during week 8, and 7 mg per day during week 9) or placebo. The target day for quitting smoking was usually day 8. RESULTS: The abstinence rates at 12 months were 15.6 percent in the placebo group, as compared with 16.4 percent in the nicotine-patch group, 30.3 percent in the bupropion group (P<0.001), and 35.5 percent in the group given bupropion and the nicotine patch (P<0.001). By week 7, subjects in the placebo group had gained an average of 2.1 kg, as compared with a gain of 1.6 kg in the nicotine-patch group, a gain of 1.7 kg in the bupropion group, and a gain of 1.1 kg in the combined-treatment group (P<0.05). Weight gain at seven weeks was significantly less in the combined-treatment group than in the bupropion group and the placebo group (P<0.05 for both comparisons). A total of 311 subjects (34.8 percent) discontinued one or both medications. Seventy-nine subjects stopped treatment because of adverse events: 6 in the placebo group (3.8 percent), 16 in the nicotine-patch group (6.6 percent), 29 in the bupropion group (11.9 percent), and 28 in the combined-treatment group (11.4 percent). The most common adverse events were insomnia and headache. CONCLUSIONS: Treatment with sustained-release bupropion alone or in combination with a nicotine patch resulted in significantly higher long-term rates of smoking cessation than use of either the nicotine patch alone or placebo. Abstinence rates were higher with combination therapy than with bupropion alone, but the difference was not statistically significant.

The smoking cessation efficacy of varying doses of nicotine patch delivery systems 4 to 5 years post-quit day.

BACKGROUND: This study was undertaken to evaluate the long-term smoking cessation efficacy of varying doses of transdermal nicotine delivery systems 4 to 5 years post-quit day. METHODS: A follow-up study was conducted 48 to 62 months after quit day among patients who were enrolled in the Transdermal Nicotine Study Group investigation. The latter study included group smoking cessation counseling and randomized assignment to 21, 14, or 7 mg nicotine patches or placebo patches. Seven of nine smoking cessation research centers participated in the long term follow-up investigation. RESULTS: The self-reported continuous quit rate among patients originally assigned 21 mg (20.2%) was significantly higher than rates for patients assigned 14 mg (10.4%), 7 mg (11.8%), or placebo patches (7.4%). Log rank survival analysis found no difference in relapse rates after 1 year postcessation. Smokers under age 30 years were significantly less likely to be abstinent at long term follow-up compared to smokers > or = 30 years of age (3 vs 13%, respectively). Mean weight gain in confirmed continuous quitters was 10.1 kg in men and 8.0 kg in women. Of the 63 continuous abstainers surveyed, 30 respondents (48%) reported that they no longer craved cigarettes, and no individual reported daily craving for cigarettes. CONCLUSIONS: Nicotine patch therapy with 21 mg/day patches resulted in a significantly higher long-term continuous abstinence rate compared to lower dose patches and placebo. Relapse rates among the various treatment conditions were similar after 1 year postcessation.

Self-recognition of alcohol and cigarette dependency among high school seniors.

A brief, anonymous survey of 284 high school seniors at one midwestern metropolitan public high school assessed current smoking, history of alcohol use, and students' beliefs in future risk of dependency. A major purpose was to assess students' self-recognition of alcohol and cigarette dependency. Of the seniors surveyed, 92 (32%) were current smokers, and 237 (84%) reported a previous history of alcohol use. 52% of current smokers indicated they were already "hooked" on cigarettes or anticipated a good chance of cigarette addiction five years later. In contrast, 94% of regular alcohol users indicated there was either no chance (71%) or only a mild chance (23%) of ever becoming an alcoholic. Six of every ten high school smokers surveyed reported that quitting cigarettes for three days would be difficult.

Physician reporting of and referral for patient complaints about sleep disorders.

The first goal of this Nebraska-based study was to determine physician reporting of patient complaints about sleep. The second goal was to determine the patterns of referral to sleep disorders laboratories by geographic location and specialty practice. A total of 299 Nebraska physicians (177 in urban areas and 122 in rural areas) completed a questionnaire concerning sleep complaints among patients. We found no statistically significant differences between urban and rural physicians in the percentage of patients reporting insomnia, excessive daytime sleepiness, snoring, or other sleep complaints. Psychiatrists reported on significantly more patients with insomnia and excessive daytime sleepiness than did other physicians; however, they tended to refer fewer patients to sleep disorders laboratories than did physicians practicing internal medicine. Urban physicians referred significantly more patients to sleep disorders laboratories than did rural physicians. We concluded that physician reporting of patient complaints about sleep is similar in urban and rural areas of Nebraska. However, physicians in rural areas tend to refer fewer patients to sleep disorders laboratories than do physicians in urban communities.

General vs local anesthesia. Effect on bronchoalveolar lavage findings.

Bronchoalveolar lavage (BAL) can be performed with the patient undergoing either local or general anesthesia (GA). This study investigates whether the type of anesthesia affects BAL fluid and cell recovery. Eighty patients, were selected for study. Fluid recoveries were significantly less in the GA group for both the bronchial and alveolar lavages. The differences were confirmed for BAL fluid recovery in a subsequent group of 120 unselected patients. Bronchoscope size did not appear to affect recovery, nor did anesthesia time; BAL fluid recovery from patients with respiratory failure who were intubated and mechanically ventilated was similar to that in the GA group, suggesting that lower recovery rates may be due to mechanical ventilation. The BAL fluid cell counts were related to fluid recovery, but airway neutrophils represented a higher percentage of BAL lavage fluid cells in the GA lavages, independent of differences in the volume of lavage fluid recovered.

Transdermal clonidine reduced some withdrawal symptoms but did not increase smoking cessation.

BACKGROUND: Clonidine may be useful in controlling tobacco withdrawal and in facilitating smoking cessation. This study was developed to test the efficacy of transdermal clonidine in promoting smoking cessation. METHODS: We conducted a five-center, double-blind, placebo-controlled, randomized controlled trial of transdermal clonidine in conjunction with a minimal behavioral intervention for smoking cessation. The intervention was based on the American Lung Association's Freedom From Smoking program. Self report of not smoking was validated with exhaled air carbon monoxide of less than 8 ppm and salivary cotinine of less than 20 ng/mL. Transdermal clonidine therapy began 1 week before the target quit date: 0.1 mg/24 h for the first 4 days increasing to 0.2 mg/24 h for the next 3 days, if the lower dose was tolerated. The highest tolerated dose was then continued for 6 weeks after target quit day. Withdrawal symptoms were measured daily for the first 7 days after target quit day. RESULTS: A total of 213 patients were enrolled (106 active drug and 107 placebo). During the study, 15.5% of patients had drug therapy discontinued due to adverse effects, 24.5% (26/106) taking active drug vs 8.4% (9/107) receiving placebo. There was a significant reduction in anxiety score from 3.0 to 2.4 (placebo vs active) and irritability score from 2.2 to 1.7 (placebo vs active) during the first week after cessation. There was no reduction in other withdrawal symptoms. The overall 12-week abstinence rate was 33.0% (35/106) in the active drug group vs 34.5% (37/107) in the placebo group (not significant). CONCLUSION: This study demonstrated some reduction in early withdrawal symptoms with the use of a clonidine transdermal patch, but no increase in cessation rate, 6 weeks after medication had been discontinued.

Altered epithelial lining fluid parameters in old normal individuals.

Pneumonia is a leading cause of morbidity and death in older patients, and immunosenescence is believed to contribute to their susceptibility. In order to investigate whether age-related changes occur on the epithelial surfaces of the lung, bronchoscopy and bronchoalveolar lavage (BAL) were performed without complication in 19 young (27.7 +/- 4.2 yrs), 6 middle-aged (49.8 +/- 3.5 yrs), and 8 old (74.1 +/- 4.3 yrs) normal, nonsmoking subjects. BAL was performed by instilling and retrieving five 20 ml aliquots of normal saline into three sites. The returns from the first aliquots (the bronchial sample) were analyzed separately from the returns from the subsequent aliquots (the distal sample). Lavage fluid cellularity was characterized and IgA, IgG, and albumin were measured by ELISA. Lavage fluid returns were lower in the elderly group and correlated with spirometric parameters. Significantly elevated numbers of neutrophils were recovered by the bronchial sample fluid from the old group. In contrast, no consistent difference in macrophage recovery by either the bronchial or distal sample was noted. In both the bronchial and distal samples, IgG, but not IgA or albumin, was elevated in the group of old subjects. Alterations occurring in BAL fluid with aging may reflect changes in local host defenses.

Total indoor smoking ban and smoker behavior.

METHODS: To assess smoking policy support and effects, 1,083 hospital employees (203 smokers) were surveyed by anonymous questionnaire 1 year after the announcement (5 months after implementation) of a new total indoor smoking ban. A second follow-up, limited to smoker respondents only, was conducted 2 years postannouncement. RESULTS: A total indoor smoking ban was supported by the vast majority of nonsmokers (89%) and ex-smokers (86%) and by nearly half of the then-smoking population (45%). Consistent with previous reports, the smoking ban was associated with a significant decrease in cigarette use during work hours, particularly among moderate to heavy smokers. However, the ban did not result in increased institutional quit rates. Light smokers (< 10 cig/day), compared with heavy smokers (> or = 30 cig/day), were more likely to support the no-smoking policy and had fewer problems observing the ban. They were also less apt to report a decrease in work productivity. CONCLUSION: A total indoor smoking ban had little effect on overall institutional quit rates. Heavy smokers will, predictably, experience the greatest difficulty complying with a total indoor nonsmoking policy.

[Effects of transdermal nicotine as an adjunct in smoking cessation therapy. A double-blind randomized study controlled with placebo]. / Effetti del rilascio transdermico di nicotina come terapia di supporto per lo svezzamento dal fumo di sigaretta. Uno studio randomizzato in doppio cieco con controlli trattati con placebo.

To assess the smoking cessation efficacy of transdermal nicotine patches an adjunct to low-intervention therapy, we conducted a double-blind, placebo-controlled trial in 158 smokers. Participants were randomly assigned to one of the following three study regimens that required daily application of two 15-cm2 patches: 1) 24-hour nicotine delivery, 2) nicotine delivery during wakeful hours only, and 3) placebo. The impact of the three regimens on smoking cessation rates and tobacco withdrawal symptoms was examined. During the last 2 weeks of the trial, 39% of the 24-hour nicotine regimen delivery group, 35% of those on wakeful hour nicotine regimens, and 13.5% of the placebo treatment group achieved abstinence. Self-reported quit rates for the two nicotine patch-wearing regimens, as compared with that for the placebo group, continued to be significantly higher at 6 months. Moreover, compared with placebo, the transdermal nicotine patches significantly reduced tobacco withdrawal symptoms during the first few weeks of quitting. The differences in quit rates and tobacco withdrawal symptoms between the to active groups were not statistically significant. The patches were well tolerated both topically and systemically. We concluded that transdermal nicotine, when used as an adjunct to low-intervention therapy, significantly reduced tobacco withdrawal symptoms and enhanced smoking cessation rates.

Chronic inflammation is associated with an increased proportion of goblet cells recovered by bronchial lavage.

To evaluate the possibility that bronchoalveolar lavage could provide sufficient respiratory epithelial cells to quantify changes in epithelial cell types associated with chronic inflammation, we examined the epithelial cells obtained in the first infused (20 ml) aliquots that were processed separately from later aliquots, a process known to enrich for bronchial contents. Epithelial cells, including ciliated cells, goblet cells, and fragments of desquamated epithelium, were easily identified after preparation by cytocentrifugation and staining with a modified Giemsa stain. Quantification of the columnar cell types revealed that those with chronic bronchitis and asymptomatic smokers have increased goblet cells as a percentage of the total columnar epithelial cells (chronic bronchitics 36 +/- 2 percent, asymptomatic smokers 22 +/- 2 percent) compared with normal subjects (9 +/- 1 percent, p less than 0.001, ANOVA). Significantly, the goblet cell percentage was strongly correlated with other measures of bronchitis and measures of airflow obstruction such as the bronchitis index, a visually derived score at bronchoscopy of airway inflammation (r = 0.72, p less than 0.001), the percent neutrophils in the first infused aliquots (r = 0.44, p less than 0.05), and the FEV1 percent (r = -0.74, p less than 0.001). Thus, bronchoalveolar lavage is capable of providing sufficient bronchial epithelial cells for analysis, and the changes seen in the spectrum of columnar epithelial cells may reflect important underlying pathologic changes.

Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy. A randomized, placebo-controlled, double-blind study.

To assess the smoking cessation efficacy of transdermal nicotine patches as an adjunct to low-intervention therapy, we conducted a double-blind, placebo-controlled trial in 158 smokers. Participants were randomly assigned to one of the following three study regimens that required daily application of two 15-cm2 patches: (1) 24-hour nicotine delivery, (2) nicotine delivery during wakeful hours only, and (3) placebo. The impact of the three regimens on smoking cessation rates and tobacco withdrawal symptoms was examined. During the last 2 weeks of the trial, 39% of the 24-hour nicotine regimen delivery group, 35% of those on wakeful hour nicotine regimens, and 13.5% of the placebo treatment group achieved abstinence. Self-reported quit rates for the two nicotine patch-wearing regimens, as compared with that for the placebo group, continued to be significantly higher at 6 months. Moreover, compared with placebo, the transdermal nicotine patches significantly reduced tobacco withdrawal symptoms during the first few weeks of quitting. The differences in quit rates and tobacco withdrawal symptoms between the two active groups were not statistically significant. The patches were well tolerated both topically and systemically. We concluded that transdermal nicotine, when used as an adjunct to low-intervention therapy, significantly reduced tobacco withdrawal symptoms and enhanced smoking cessation rates.

Evaluation of elastase and antielastase balance in patients with chronic bronchitis and pulmonary emphysema.

On the basis of the "protease-antiprotease imbalance" theory for the pathogenesis of pulmonary emphysema, we hypothesized that measurement of elastase burden and antielastase capacity in the alveolar space might correlate with emphysema. To evaluate this, the severity of emphysema, the elastase burden, and the elastase inhibitory capacity were estimated in 28 patients with chronic bronchitis and variable degrees of emphysema, none of whom had congenital deficiency of alpha-1-protease inhibitor, and all of whom underwent bronchoalveolar lavage. Emphysema was assessed by both computed tomography and diffusing capacity. To examine "elastase burden," elastase:alpha-1-protease inhibitor complex and free elastase activity in alveolar lavage fluids were measured. To evaluate "antielastase" capacity, elastase inhibiting capacity in alveolar lavage fluid was measured. Elastase burden correlated directly and antielastase capacity correlated inversely with emphysema. These data provide direct support for the "protease-antiprotease imbalance" theory of emphysema in a group of smokers without congenital deficiency of alpha-1-protease inhibitor.

Smoking cessation in the workplace: evaluation of relapse factors.

Relapse factors associated with a well-supported worksite smoking cessation program were examined in a prospective study. Of 104 employee-participants, 81 (78%) were confirmed as abstinent at 8 days after quit day. Forty-six employees (44%) continued to report total abstinence at 1 year. Stepwise regression analysis of baseline variables found two significant, but weak, predictors of 1-year smoking status: Fagerstrom score and number of other smokers residing in the home. Analysis of tobacco withdrawal symptom data of confirmed abstainers found only self-reported anxiety scores to be predictive of smoking status at 1 year. Early abstainers with elevated anxiety scores appear to be at high risk for smoking relapse.

In vivo and in vitro methods for evaluating airways inflammation: implications for respiratory toxicology.

The lung is frequently the target of injury for toxic exposures. Often these exposures lead to significant disease. Assessment of toxic exposures to the lung, however, may be made using both in vitro and in vivo methods. Recent advances in respiratory cell biology have made possible in vitro analyses of the interactions between airway cells and potential toxins. In addition, the lung can be sampled in vivo using bronchoscopy and bronchoalveolar lavage. This opens up the possibility of assessing potential toxins prior to the development of clinically significant disease. Together, these advancing methodologies promise new potential for the assessment and evaluation of toxic exposures to the lung.