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There is a strong link between cigarette smoking and pulmonary complications among people living with HIV. However, the effects of smoking on the local lung immune environment in this population remain unclear. Bronchoalveolar lavage and saliva were collected from HIV-infected smokers involved in a prospective study investigating alveolar macrophage expression of host defense molecules. Salivary cotinine concentrations were inversely related to expression of the immune cell receptor nucleotide-binding oligomerization domain-2 and the cathelicidin antimicrobial peptide LL-37. The negative correlation between salivary cotinine and LL-37 was particularly strong. Our study provides insight into how nicotine may adversely affect lung innate immunity in HIV.

Background Hypogammaglobulinemia (serum IgG levels Research Question To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD. Study Design and Methods Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status. Results The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P Interpretation Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions.

Background Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear. Research Question Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes? Study Design and Methods We conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site. Results The trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66). Interpretation Among patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.

Background The National Emphysema Treatment Trial (NETT) showed a clear survival and quality of life benefit for patients selected for lung volume reduction surgery (LVRS). However, long-term outcomes after LVRS are still lacking. The aim of this study was to evaluate overall mortality and functional durability in this single-institution cohort of patients undergoing LVRS. Methods A single-institution registry identified all patients who had undergone LVRS from January 2006 through August 2017. Records were retrospectively reviewed, and data were collected to include pulmonary functions test values, he University of California, San Diego shortness of breath questionnaire and complication and mortality rate. Results LVRS was performed in 135 patients with a 2.2% 90-day mortality rate (n = 3). Estimated 1-, 2- and 5-year survival was 0.94 (95% confidence interval [CI], 0.88 to 0.97), 0.91 (95% CI, 0.83 to 0.95), and 0.71 (95% CI, 0.57 to 0.81), respectively. Mean improvement in forced expiratory volume in 1 second% predicted from preoperative baseline at 1 and 2 years was 5.3 (95% CI, 3.1 to 7.4) and 4.3 (95% CI, 1.9 to 6.6), respectively. There was a mean improvement in maximum workload of 5.2 W (95% CI, 0.9 to 9.4) at 1 year. Also, shortness of breath questionnaire scores had a mean decrease of −17.3 points (95% CI, −21.8 to −13) at 6 months and −13.9 points (95% CI, −18.4 to −9.3) at 1 year. Conclusions LVRS is an effective operation with overall improvement in functional status and quality of life in appropriately selected patients.

BackgroundAlthough inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear.Research questionAre inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes?Study design and methodsWe conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vslow) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site.ResultsThe trial enrolled 738 patients (73.4%men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95%CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64%higher risk of pneumonia (incidence rate ratio, 1.64; 95%CI, 1.01-2.66).InterpretationAmong patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.

Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease. Frequent pneumonias and exacerbations are known to accelerate its progression. We present a case of severe emphysema whose lung function paradoxically improved following recurrent pneumonia, without lung volume reduction surgery (LVRS). A 54-year-old female with severe COPD presented for LVRS evaluation. She was not a candidate for the surgery because of the unsuitable anatomic distribution of her emphysema. The patient experienced recurrent pneumonia over the years but her lung function and oxygen requirement showed marked improvement. Follow-up imaging studies showed decreased lung volumes and focal fibrotic changes. We believe that the improvement in her lung function overtime is the reflection of lung volume reduction as a result of parenchymal remodeling due to repeated lung infection. These findings seen in our patient contribute important information for the continued effort in developing nonsurgical lung volume reduction techniques.

OBJECTIVE To examine the prognostic value of select biobehavioral factors in patients with chronic obstructive pulmonary disease (COPD) in a secondary analysis of participants from the INSPIRE-II trial. METHODS Three hundred twenty-six outpatients with COPD underwent assessments of pulmonary function, physical activity, body mass index, inflammation, pulmonary symptoms, depression, and pulmonary quality of life and were followed up for up to 5.4 years for subsequent clinical events. The prognostic value of each biobehavioral factor, considered individually and combined, also was examined in the context of existing Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 risk stratification. RESULTS Sixty-nine individuals experienced a hospitalization or died over a mean follow-up period of 2.4 (interquartile range = 1.6) years. GOLD classification was associated with an increased risk of clinical events (hazard ratio [HR] = 2.72 [95% confidence interval = 1.63-4.54], per stage); 6-minute walk (HR = 0.50 [0.34-0.73] per 500 ft), total steps (HR = 0.82 [0.71-0.94] per 1000 steps), high-sensitivity C-reactive protein (HR = 1.44 [1.01-2.06] per 4.5 mg/l), depression (HR = 1.12 [1.01-1.25] per 4 points), and pulmonary quality of life (HR = 1.73 [1.14-2.63] per 25 points) were each predictive over and above the GOLD assessment. However, only GOLD group and 6-minute walk were predictive of all-cause mortality and COPD hospitalization when all biobehavioral variables were included together in a multivariable model. CONCLUSIONS Biobehavioral factors provide added prognostic information over and above measures of COPD severity in predicting adverse events in patients with COPD.

Rationale Characteristics associated with adherence to long-term oxygen therapy (LTOT) in COPD remain unclear. Objectives To identify patient characteristics at the time of oxygen initiation associated with its adherence. Methods We conducted a secondary analysis of data from 359 COPD participants assigned to oxygen in the Long-term Oxygen Treatment Trial. Participants were prescribed continuous (n = 214) or intermittent (n = 145) oxygen based on desaturation patterns at study entry. At the time of initial prescription, participants rated their perceived readiness, confidence, and importance to use oxygen on a 0–10 scale (0 = not at all, 10 = very much). During follow-up, they self-reported average hours per day of use (adherence). Adherence was averaged over short-term (0–30 days), medium-term (months 9–12), and long-term (month 13 to last follow-up) intervals. Multivariable logistic regression models explored characteristics associated with high adherence (≥16 h/day [continuous] or ≥8 h/day [intermittent]) during each time interval. Results Participant readiness, confidence, and importance at the time of oxygen initiation were associated with high short- and medium-term adherence. For each unit increase in baseline readiness, the odds of high short-term adherence increased by 21% (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.05–1.40) and 94% (OR 1.94, 95% CI 1.45–2.59) in the continuous and intermittent groups, respectively. In both groups, high adherence in the medium-term was associated with high adherence in the long-term (continuous, OR 12.49, 95% CI 4.90–31.79; intermittent, OR 38.08, 95% CI 6.96–208.20). Conclusions Readiness, confidence, and importance to use LTOT at initiation, and early high adherence, are significantly associated with long-term oxygen adherence.

Author(s): Drummond, M Bradley; Huang, Laurence; Diaz, Philip T; Kirk, Gregory D; Kleerup, Eric C; Morris, Alison; Rom, William; Weiden, Michael D; Zhao, Enxu; Thompson, Bruce; Crothers, Kristina | Abstract: ObjectiveHIV-infected individuals are susceptible to development of chronic lung diseases, but little is known regarding the prevalence and risk factors associated with different spirometric abnormalities in this population. We sought to determine the prevalence, risk factors and performance characteristics of risk factors for spirometric abnormalities among HIV-infected individuals.DesignCross-sectional cohort study.MethodsWe analyzed cross-sectional US data from the NHLBI-funded Lung-HIV consortium - a multicenter observational study of heterogeneous groups of HIV-infected participants in diverse geographic sites. Logistic regression analysis was performed to determine factors statistically significantly associated with spirometry patterns.ResultsA total of 908 HIV-infected individuals were included. The median age of the cohort was 50 years, 78% were men and 68% current smokers. An abnormal spirometry pattern was present in 37% of the cohort: 27% had obstructed and 10% had restricted spirometry patterns. Overall, age, smoking status and intensity, history of Pneumocystis infection, asthma diagnosis and presence of respiratory symptoms were independently associated with an abnormal spirometry pattern. Regardless of the presence of respiratory symptoms, five HIV-infected participants would need to be screened with spirometry to diagnose two individuals with any abnormal spirometry pattern.ConclusionsNearly 40% of a diverse US cohort of HIV-infected individuals had an abnormal spirometry pattern. Specific characteristics including age, smoking status, respiratory infection history and respiratory symptoms can identify those at risk for abnormal spirometry. The high prevalence of abnormal spirometry and the poor predictive capability of respiratory symptoms to identify abnormal spirometry should prompt clinicians to consider screening spirometry in HIV-infected populations.

Despite the immune-reconstitution with antiretroviral therapy (ART), HIV-infected individuals remain highly susceptible to tuberculosis (TB) and have an enrichment of oral anaerobes in the lung. Products of bacterial anaerobic metabolism, like butyrate and other short-chain fatty acids (SCFAs), induce regulatory T cells (Tregs). We tested whether SCFAs contribute to poor TB control in a longitudinal cohort of ART-treated HIV-infected South Africans. Increase in serum SCFAs was associated with increased TB susceptibility. SCFAs inhibited IFN-γ and IL-17A production in peripheral blood mononuclear cells from HIV-infected ART-treated individuals in response to M. tuberculosis antigen stimulation. Pulmonary SCFAs correlated with increased oral anaerobes, such as Prevotella in the lung, and with M. tuberculosis antigen-induced Tregs. Metabolites from anaerobic bacterial fermentation may, therefore, increase TB susceptibility by suppressing IFN-γ and IL-17A production during the cellular immune response to M. tuberculosis.

To date, no study has evaluated the short- and long-term effects air pollution exposure on emphysematous subjects who have undergone lung volume reduction surgery (LVRS). Data from the National Emphysema Treatment Trial study (1998-2003) included 1,218 subjects, aged 39 to 84. Daily values of ambient fine particulate matter (aerodynamic diameter < 2.5 μm; PM2.5) and ozone were obtained. Mixed-effects models tested the association between short- and long-term pollutant concentrations and changes in pulmonary function. Cumulative air pollution exposure was strongly associated with worsened respiratory function and symptoms. Mean PM2.5 was associated with poorer lung function. Lagged exposures were poorly associated with respiratory health outcomes. There were detrimental respiratory and pulmonary effects observed in response to even low levels of ambient air pollutants among study participants. These results are indicative that exposures even below those of air quality standards may still pose significant risks to severe chronic obstructive pulmonary disease (COPD) subjects.

Reactive oxygen species (ROS) exist as natural mediators of metabolism to maintain cellular homeostasis. However, ROS production may significantly increase in response to environmental stressors, resulting in extensive cellular damage. Although several potential sources of increased ROS have been proposed, exact mechanisms of their generation have not been completely elucidated. This is particularly true for diaphragmatic skeletal muscle, the key muscle used for respiration. Several experimental models have focused on detection of ROS generation in rodent diaphragm tissue under stressful conditions, including hypoxia, exercise, and heat, as well as ROS formation in single myofibres. Identification methods include direct detection of ROS with confocal or fluorescent microscopy and indirect detection of ROS through end product analysis. This article explores implications of ROS generation and oxidative stress, and also evaluates potential mechanisms of cellular ROS formation in diaphragmatic skeletal muscle.

Objective To investigate the molecular redox mechanisms in allergic asthma and to examine current studies of the disease to provide a basis for further investigation of oxidative stress in allergic asthma and the signaling cascades involved in its pathogenesis. Data Sources Through the use of PubMed, a broad biomedical literature review was conducted in the following areas related to the physiology and pathobiology of asthma: redox therapy, reactive oxygen species (ROS), oxidative stress, allergic asthma, and antioxidants. Study Selections Studies pertaining to oxidative stress and redox signaling in the molecular pathways of inflammation and hypersensitivity in the pathogenesis of allergic asthma were reviewed. Results Allergic asthma is associated with an increase in endogenous ROS formation, leading to oxidative stress–induced damage to the respiratory system and mitigated antioxidant defenses. Exposure to environmental antigens has been shown to stimulate overproduction of ROS, resulting in abnormal physiologic function of DNA, proteins, and lipids that clinically can augment bronchial hyperresponsiveness and inflammation. Through the use of animal and human studies, oxidative stress has been determined to be important in the pathogenesis of allergic asthma. Thus, recent research suggests that the assessment of oxidative stress byproducts represents a novel method by which disease severity can be monitored. In addition, the use of redox-based therapy to attenuate levels of ROS presents a potential strategy to alleviate oxidative stress–induced airway inflammation in patients with asthma. Conclusion Redox mechanisms of oxidative stress in allergic asthma appear to play a key role in the pathogenesis of the disease and represent a promising therapeutic target.

Background. HIV-infected subjects have an increased incidence of pulmonary emphysema. There are known gender differences in COPD phenotypic expression and diagnosis, but this is not well characterized in lung disease related to HIV. We analyzed a group at risk for the development of COPD (HIV-infected smokers) to determine gender differences in pulmonary symptoms, pulmonary function tests, and HRCT appearances.Methods. This was a cross-sectional, baseline analysis of a prospective study performed between 2006 and 2010. We performed symptomatic, pulmonary function, and computed tomography assessments in 243 HIV-infected smokers. In a subset bronchoalveolar lavage was performed with proteomic analysis of their alveolar macrophages.Results. The majority of the participants were male 213 (87.6%). There was significantly higher percentage of cough and phlegm production in males. There was also a lower FEV1 and a higher RV in males than females. Proteomic analysis revealed 29 proteins with at least a 2-fold higher expression in males and 13 identified proteins that were higher in females.Conclusions. In this group of HIV-infected smokers, airway symptoms and pulmonary function test abnormalities were higher in men than women. These gender differences may be due to differential expression of certain proteins in this group.

The smoking prevalence estimates among HIV-infected individuals range from 40%-84%; much higher than the overall adult prevalence in the United States. Characteristics that are associated with smokers who are HIV-positive include drug and alcohol abuse, psychiatric comorbidities, and lower education and socioeconomic status. There are important health implications for HIV-infected smokers, including bacterial and Pneumocystis pneumonia, tuberculosis, COPD, lung cancer and coronary artery disease. To date, there have been few tobacco dependence treatment trials conducted among HIV-infected smokers. Most have used nicotine replacement therapy but abstinence rates were low. A recent preliminary study found the use of varenicline to be well tolerated and it may increase abstinence rates with HIV-infected individuals. Recommendations for future research include examining underlying factors that contribute to persistent smoking and barriers to abstinence, identifying ways to increase motivation for quit attempts, increasing the number of multi-centered, two-arm tobacco dependence treatment trials, and using highly efficacious first-line pharmacotherapy in tobacco dependence treatment intervention studies. Addressing the above-mentioned research gaps will help to reduce the tobacco-related disease burden of HIV-infected individuals in the future.

High prevalence of tobacco use and low success in quitting remain significant problems for reducing disease burden among HIV-infected persons. This study’s purpose was to examine participant responsiveness and tobacco dependence treatment adherence and their influences on tobacco abstinence among HIV-infected patients. This non-randomized study included HIV-infected smokers 18 years of age or older, who smoked at least 5 cigarettes per day, and had an interest in quitting smoking in the next 30 days. HIV-infected smokers (n = 247) received a 12-week tobacco dependence treatment intervention that included pharmacotherapy and telephone counseling. Younger age and non-White race were associated with lower adherence to pharmacotherapy. Younger age, non-White race, and increased monthly binge drinking were associated with lower adherence to telephone counseling. High participant responsiveness was associated with adherence to pharmacotherapy, counseling, and abstinence. Development and testing of interventions to improve adherence to evidence-based tobacco dependence treatment is warranted.

INTRODUCTION The prevalence of smoking is high among the human immunodeficiency virus (HIV)-infected population, yet there are few studies of tobacco dependence treatment in this population. This paper reports the safety of varenicline versus nicotine replacement therapy (NRT) and describes preliminary results about the effectiveness of varenicline versus NRT in HIV-infected smokers. METHODS Participants completed 12 weeks of telephone counseling and either varenicline or NRT. Varenicline was encouraged as the preferred intervention; NRT was used for those unable/unwilling to take varenicline. Adverse events (AEs), related to pharmacotherapy, were monitored. Biochemically confirmed abstinence at 3 months was examined. Inverse probability of treatment weighted logistic regression models was fit to compare participants on varenicline to those on NRT. RESULTS Among participants on varenicline (n = 118), the most common AEs were nausea, sleep problems, and mood disturbances. One person reported suicidal ideation; there were no cardiovascular complications. There were no differences in the varenicline AE profile between participants on combination antiretroviral therapy (ART) and those not on ART. The percentages of confirmed abstainers were 11.8% in the NRT group and 25.6% in the varenicline group. The odds of being abstinent were 2.54 times as great in the varenicline group compared with the NRT group in the propensity weighted model (95% CI 1.43-4.49). CONCLUSIONS In this preliminary study, the safety profile of varenicline among HIV-infected smokers resembles findings among smokers without HIV. In addition, varenicline may be more effective at promoting abstinence in this population. Future randomized clinical trials are warranted.

The spectrum of lung diseases associated with HIV is broad, and many infectious and noninfectious complications of HIV infection have been recognized. The nature and prevalence of lung complications have not been fully characterized since the Pulmonary Complications of HIV Infection Study more than 15 years ago, before antiretroviral therapy (ART) increased life expectancy. Our understanding of the global epidemiology of these diseases in the current ART era is limited, and the mechanisms for the increases in the noninfectious conditions, in particular, are not well understood. The Longitudinal Studies of HIV-Associated Lung Infections and Complications (Lung HIV) Study (ClinicalTrials.gov number NCT00933595) is a collaborative multi-R01 consortium of research projects established by the National Heart, Lung, and Blood Institute to examine a diverse range of infectious and noninfectious pulmonary diseases in HIV-infected persons. This article reviews our current state of knowledge of the impact of HIV on lung health and the development of pulmonary diseases, and highlights ongoing research within the Lung HIV Study.

As mortality due to AIDS-related causes has decreased with the use of antiretroviral therapy, there has been a rise in deaths related to non-AIDS-defining illnesses. Given the exceedingly high prevalence of cigarette smoking among individuals living with HIV infection, tobacco has been implicated as a major contributor to this paradigm shift. Evidence suggests that smoking-related illnesses, such as cardiovascular disease, respiratory illnesses, and certain malignancies, contribute substantially to morbidity and mortality among HIV-infected persons. In this review, we summarize the adverse health consequences of smoking relevant to HIV-infected individuals and discuss smoking cessation in this unique population, including a discussion of barriers to quitting and a review of studies that have examined smoking cessation interventions.

The prevalence of tobacco use in women has increased over the past century. This has resulted in dramatic increases in smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD) and lung cancer. There is growing literature suggesting that women may be more susceptible than men to the effects of tobacco and to the development of COPD. Women may also have specific barriers that interfere with smoking cessation. This article addresses possible differences in lung function decline and nicotine metabolism in women compared to men. Differences in COPD between the sexes are discussed. Finally, barriers to smoking cessation in women are presented.

Background CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of −950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV 1 and percent predicted value of FEV 1 with CT scan measures of emphysema and airway disease. Results In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT ( r = −0.28, p = 0.0001) and SRWA ( r = −0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV 1 % predicted (R = −0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = −5.2, p = 0.009; β = −2.6, p = 0.008, respectively) and %LAA-950 (β = −10.6, p = 0.03) with the postbronchodilator FEV 1 % predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema.

Background Chronic Obstructive Pulmonary Disease (COPD) is a progressive illness characterized by airflow obstruction and dyspnea that afflicts over 12 million people and represents a leading cause of death in the United States. Not surprisingly, COPD is often associated with emotional distress and reduced psychosocial adjustment, which can negatively impact physical functioning and impair quality of life. However, the psychosocial consequences of COPD remain largely untreated. A previous randomized trial from our research team demonstrated that coping skills training (CST) can improve pulmonary-specific quality of life among pulmonary patients awaiting lung transplant (the INSPIRE study). To date, however, no studies have examined the effects of a caregiver-assisted CST intervention in patients with COPD with less severe disease. Purpose INSPIRE II is a randomized clinical trial (RCT) funded by the NHLBI to evaluate the effects of telephone-based enhanced CST for patients with COPD and their caregivers compared to standardized medical care (SMC) including COPD education and symptom monitoring on medical outcomes, physical functioning, and quality of life. Methods Six hundred COPD patients and their respective caregivers recruited from Duke University and Ohio State University will be evaluated and randomized (in a 1:1 ratio) to enhanced CST (including sessions promoting physical activity, relaxation, cognitive restructuring, communication skills, and problem solving) or to SMC. The primary outcomes include all-cause mortality, COPD-related hospitalizations/ physician visits, and quality of life. These endpoints will be measured through self-report questionnaires, behavioral measures of functional capacity (i.e., accelerometer and six minute walk test) and pulmonary function tests (e.g., FEV1). Results This article reviews prior studies in the area and describes the design of INSPIRE-II. Several key methodological issues are discussed including the delivery of CST over the telephone, encouraging physical activity, and inclusion of caregivers as patient coaches to enhance the effectiveness of the intervention. Limitations We recognize that SMC does not adequately control for attention, support, and non-specific factors, and that, in theory, non-specific effects of the intervention could account for some, or all, of the observed benefits. However, our fundamental question is whether the telephone intervention produces benefits over-and-above the usual care that patients typically receive. The SMC condition will provide education and additional weekly telephone contact, albeit less than the attention received by the CST group. We recognize that this attention control condition may not provide equivalent patient contact, but it will minimize group differences due to attention. We considered several alternative designs including adding a third usual care only arm as well as an education only control arm. However, these alternatives would require more patients, reduce the power to detect significant effects of our primary medical endpoints, and add a significant additional expense to the cost of the study that would make such an undertaking neither scientifically or financially viable. Conclusions We believe that this novel approach to patient care in which caregivers are used to assist in the delivery of coping skills training to patients with COPD has the potential to change the way in which COPD patients are routinely managed in order to reduce distress, enhance quality of life, and potentially improve medical outcomes. Clinical Trials 2009; 6: 172—184. http:// ctj.sagepub.com

The treatment objectives for chronic obstructive pulmonary disease (COPD) include relieving symptoms such as dyspnea and cough, slowing the accelerated decline in lung function, decreasing exacerbations, and improving quality of life. All major guidelines for COPD management recommend beginning treatment with bronchodilators. There are several classes of bronchodilators, including beta-agonists, anticholinergics, and phosphodiesterase inhibitors, each with a specific mechanism of action. The overall approach to managing stable COPD involves a stepwise increase in treatment. Because of the progressive nature of emphysema, such an approach often involves combining bronchodilators from different pharmacologic classes. This review focuses on the pharmacologic properties of various bronchodilators and on recent studies that have examined combination therapy as a means to optimize treatment.

The cardiac manifestations of chronic obstructive pulmonary disease (COPD) are numerous. Impairments of right ventricular dysfunction and pulmonary vascular disease are well known to complicate the clinical course of COPD and correlate inversely with survival. The pathogenesis of pulmonary vascular disease in COPD is likely multifactorial and related to alterations in gas exchange and vascular biology, as well as structural changes of the pulmonary vasculature and mechanical factors. Several modalities currently exist for the assessment of pulmonary vascular disease in COPD, but right heart catheterization remains the gold standard. Although no specific therapy other than oxygen has been generally accepted for the treatment of pulmonary hypertension in this population, there has been renewed interest in specific pulmonary vasodilators. The coexistence of COPD and coronary artery disease occurs frequently. This association is likely related to shared risk factors as well as similar pathogenic mechanisms, such as systemic inflammation. Management strategies for the care of patients with COPD and coronary artery disease are similar to those without COPD, but care must be given to address their respiratory limitations. Arrhythmias occur frequently in patients with COPD, but are rarely fatal and can generally be treated medically. Use of beta-blockers in the management of cardiac disease, while a theoretical concern in patients with increased airway resistance, is generally safe with the use of cardioselective agents.

A wrist actigraph is a device used in sleep research studies to measure whole body movements. The purpose of this study was to evaluate the feasibility, sensitivity, and validity of wrist actigraphy during pulmonary rehabilitation (PR) upper-extremity exercise in chronic obstructive pulmonary disease (COPD) patients. In this study, 20 patients wore Octagonal Basic Motionlogger® actigraphs during two 90-minute PR sessions while the investigator recorded details of the subject's upper-extremity movements. Concurrent validity with supervised exercise records was supported for upper-extremity endurance (UEE) intensity at baseline ( r = .885, p < .001) and 1 week ( r = .935, p < .001). Criterion validity was supported for UEE ( r = .56, p = .01) and combined lower- and upper-extremity resistance ( r = .72, p < .01) compared with rank-ordered type of exercise. Wrist actigraphy is shown to be a feasible, sensitive, and valid instrument to measure upper-extremity movement during PR in COPD patients.

Background Plasma viral load and blood CD4 counts are accepted indicators of severity of illness in patients with HIV-1. Lung CD4 counts have not been evaluated in asymptomatic HIV-1 patients as indicators of disease severity. Objective To determine if lung lymphocyte counts in asymptomatic subjects with HIV compare with plasma viral loads and blood CD4 counts in predicting survival. Design Retrospective, cross-sectional analysis. Setting Midwestern urban community, December 1996 to August 1998. Participants HIV-seropositive subjects (n = 95) without AIDS-related pulmonary complications. Measurements Plasma viral load, blood hemoglobin and blood lymphocyte subtypes, lung lymphocyte subtypes from BAL, body mass index, and mortality. Results Eight of the 95 subjects (8.4%) had died at the 4-year follow-up. Lung CD4 counts were significantly related to mortality by univariable analysis (2.5 × 10 3 /mL vs 0.9 × 10 3 /mL, median values for survivors vs nonsurvivors, respectively, p = 0.010). Modeling using exact methods further showed lung CD4 counts to be a significant predictor of survival after individually adjusting for potential confounders, including plasma viral load and blood CD4 count. Conclusions Lung CD4 counts in patients with HIV-1 infection may provide an independent predictor of survival.

HIV-seropositive individuals are at an increased risk for an accelerated form of emphysema. The purpose of this study was to determine the distribution of HIV-1 RNA in lung tissues and correlate this with the histologic findings and expression of matrix metalloproteases (MMPs). Reverse transcriptase (RT) in situ PCR analysis was performed on 11 AIDS lung autopsy specimens which showed varying degrees of emphysematous changes. In each lung, HIV-1 RNA was detected. In areas of histologically normal lung, very rare HIV-1-infected cells were evident. In contrast, many HIV-1-infected cells were noted in areas of emphysema. HIV-1 gag RNA was evident primarily in macrophages; infected pneumocytes were also seen. Similarly, MMP mRNA and protein, primarily MMP-9, localized to the areas of emphysema. Colabeling experiments documented that MMP expression was found primarily in cells that were HIV-1 negative and adjacent to HIV-1-infected macrophages. These results suggest that AIDS-related emphysema may be due, in part, to direct infection by HIV-1 of, primarily, alveolar macrophages, and concomitant up-regulation of MMP expression in the neighboring, noninfected cells.

Study objectives: Evidence exists that HIV-seropositive individuals may be at increased risk for the development of precocious pulmonary emphysema. HIV infection is also associated with antioxidant deficiency in both the serum and lungs, and it is therefore possible that increased oxidant stress may contribute to parenchymal lung injury occurring in the setting of HIV. We sought to determine the regional distribution of emphysema and regional distribution of glutathione (GSH) concentrations among HIV-seropositive subjects with emphysema. Design: Cross-sectional evaluation of a prospective, longitudinal study. Setting: University teaching hospital. Subjects/measurements: HIV-seropositive subjects without AIDS-related pulmonary complications participating in a descriptive study of lung biology in HIV-seropositive individuals. Emphysema scoring and evaluation of emphysema lobar distribution was performed among 40 subjects with emphysema. Eleven subjects underwent BAL of the right middle lobe (RML) and right upper lobe (RUL) with measurement of epithelial lining fluid (ELF) GSH in each lobe. Results: We found that the mean emphysema scores were much higher in the upper lobes compared to the rest of the lung. Mean GSH levels were significantly greater in the RUL compared to the RML. The regional differences were present in both smokers and nonsmokers. Conclusions: We conclude that in the setting of HIV, emphysema is more prominent and lung GSH concentrations are higher in the upper lobes. We hypothesize that the increased GSH may represent a compensatory response to increased oxidant stress in the upper lobes. (CHEST 2004; 126:1439–1442)

Study objectives Recent evidence suggests that chronic or latent viral infection may be an important predisposing factor in the development of COPD among smokers. As such, understanding if HIV-seropositive smokers are at heightened risk for respiratory symptoms may have relevance with regard to COPD pathogenesis. The current study was done to systematically identify the prevalence of respiratory symptoms among an HIV-seropositive population and to identify associated clinical features. Design and setting Cross-sectional analysis at an academic medical center. Participants Three hundred twenty-seven HIV-seropositive individuals without a history of AIDS-related pulmonary complications. Fifty-two HIV-negative individuals with a similar age and smoking history served as a comparison group. Measurements Administration of the American Thoracic Society Division of Lung Diseases respiratory questionnaire, and pulmonary function studies. Results Respiratory symptoms including dyspnea (41.6% vs 7.7%), cough (40% vs 25%), and phlegm production (41.9% vs 23.1%) were extremely common in the HIV-group and significantly more common than in the HIV-negative group. Current or prior cigarette smoking was the most important predictor of respiratory symptoms among the HIV-seropositive group. The use of the antiretroviral agent lamivudine was associated with a significant reduction in dyspnea. Conclusion HIV-seropositive individuals are at increased risk for the development of respiratory symptoms even prior to the onset of AIDS-related pulmonary complications. This may reflect a heightened susceptibility to the effects of cigarette smoking.

Objective: The National Emphysema Treatment Trial (NETT) is a randomized, multicenter, clinical trial comparing two different methods of lung volume reduction surgery plus medical therapy to medical treatment alone in patients with advanced emphysema. The purpose of this article was to use the data obtained from the NETT to assess the ability of the single-breath diffusing capacity of the lung for carbon monoxide (DLCO) to predict the need for supplemental oxygen during rest and exercise, as well as overall exercise capacity. Methods: One thousand seventy-one patients with a mean ( SD) FEV1 of 0.76 0.24 L were studied. Results: The mean DLCO was 8.0 3.1 mL/min/mm Hg (28 10% of predicted). The mean resting PaO2 was 64 10 mm Hg. There was a positive association between DLCO and both resting PaO2 and the requirement for oxygen during a walk at 1 mile per hour (mph). The odds of requiring supplemental oxygen while walking at 1 mph was nine times greater in patients with a DLCO of 35% of predicted, after adjusting for age and gender. Eighty four percent of individuals with a DLCO of 35%. Conclusion: Our results demonstrated that patients with reduced DLCO, particularly when < 20% of predicted, are more likely to have reduced PaO2 at rest and are more likely to require supplemental oxygen with low levels of activity. Thus, DLCO is useful in evaluating whether supplemental oxygen is required for exercise. (CHEST 2003; 123:1394 –1400)

Chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and mortality and reduced quality of life (QoL). Novel interventions are needed to improve outcomes in COPD patients. The present study assessed the effects of a telephone-based coping skills intervention on psychological and somatic QoL and on the combined medical end point of COPD-related hospitalizations and all-cause mortality.We conducted a dual-site, randomized clinical trial with assessments at baseline and after 16 weeks of treatment. The study population comprised 326 outpatients with COPD aged 38 to 81 years, randomized to coping skills training (CST) or to COPD education (COPD-ED). Patients completed a battery of QoL instruments, pulmonary function tests, and functional measures and were followed up for up to 4.4 years to assess medical outcomes.The CST group exhibited greater improvements in psychological QoL compared with controls (p = .001), including less depression (Cohen d = 0.22 [95% confidence interval, or CI = 0.08-0.36]) and anxiety (d = 0.17 [95% CI = 0.02-0.33]), and better overall mental health (d = 0.17 [95% CI = 0.03-0.32]), emotional role functioning (d = 0.29 [95% CI = 0.10-0.48]), vitality (d = 0.27 [95% CI = 0.11, 0.42]), and social functioning (d = 0.21 [95% CI = 0.03-0.38]). A significant baseline psychological QoL by treatment group interaction revealed that CST with lower QoL at baseline achieved even greater improvements in psychological QoL compared with COPD-ED. CST participants also exhibited greater improvements in somatic QoL (p = .042), including greater improvements in pulmonary QoL (d = 0.13 [95% CI = 0.01-0.24]), less fatigue (d = 0.34 [95% CI = 0.18-0.50]), and less shortness of breath (d = 0.11 [95% CI = -0.01 to 0.23]) and greater improvement in distance walked on the Six-Minute Walk test (d = 0.09 [95% CI = 0.01-0.16]). However, there was no significant difference in risk of time to COPD-related hospitalization or all-cause mortality between CST (34 events) and COPD-ED (32 events; p = 0.430).A telehealth CST intervention produced clinically meaningful improvements in QoL and functional capacity, but no overall improvement in risk of COPD-related hospitalization and all-cause mortality.clinicaltrials.gov Identifier: NCT00736268.

Cigarette smoking (CS) can impact the immune system and induce pulmonary disorders such as chronic obstructive pulmonary disease (COPD), which is currently the fourth leading cause of chronic morbidity and mortality worldwide. Accordingly, the most significant risk factor associated with COPD is exposure to cigarette smoke. The purpose of the present study is to provide an updated overview of the literature regarding the effect of CS on the immune system and lungs, the mechanism of CS-induced COPD and oxidative stress, as well as the available and potential treatment options for CS-induced COPD. An extensive literature search was conducted on the PubMed/Medline databases to review current COPD treatment research, available in the English language, dating from 1976 to 2014. Studies have investigated the mechanism by which CS elicits detrimental effects on the immune system and pulmonary function through the use of human and animal subjects. A strong relationship among continued tobacco use, oxidative stress, and exacerbation of COPD symptoms is frequently observed in COPD subjects. In addition, therapeutic approaches emphasizing smoking cessation have been developed, incorporating counseling and nicotine replacement therapy. However, the inability to reverse COPD progression establishes the need for improved preventative and therapeutic strategies, such as a combination of intensive smoking cessation treatment and pharmaceutical therapy, focusing on immune homeostasis and redox balance. CS initiates a complex interplay between oxidative stress and the immune response in COPD. Therefore, multiple approaches such as smoking cessation, counseling, and pharmaceutical therapies targeting inflammation and oxidative stress are recommended for COPD treatment.

To determine if the increased susceptibility to bacterial infection in asymptomatic HIV-infected patients is associated with decreased total IgG or IgG2 levels in lung epithelial lining fluid.A decrease in lung IgG levels or subtypes has been proposed as contributing to the increased risk of bacterial lung infections in HIV-infected patients. Previous studies measuring lung lavage IgG concentrations have been inconsistent.Twenty-three HIV patients and 25 control subjects underwent BAL. Both patient groups were of similar age, and had similar pulmonary function studies and body mass index. Smokers were equally represented in both groups, and the majority of subjects in both groups were male. Total IgG and IgG2 levels in lavage fluid were assayed in both cohorts and compared using a two-tailed Student's t test.The lung lining fluid IgG level in HIV-infected patients was 0.19 +/- 0.13 microg/microg of protein (mean +/- SD) vs 0.11 +/- 0.09 microg/microg of protein in control subjects (p0.05). The IgG(2) level in HIV patients was 0.034 +/- 0.038 microg/microg of protein and 0.014 +/- 0.01 microg/microg of protein in control subjects (p = 0.054). Lavage IgG levels reflected serum IgG values (correlation coefficient, 0.56; p0.001) but did not correlate with lung immunoglobulin-producing cells.The increased susceptibility to bacterial pneumonia in asymptomatic HIV-infected individuals is neither explained by depressed total IgG levels nor a deficiency in IgG(2) levels in the lungs. The strong correlation between serum and lavage IgG levels suggests that lavage IgG derives from serum.

Numerous reports have demonstrated that prior to the development of acquired immunodeficiency syndrome (AIDS)-related pulmonary complications, human immunodeficiency virus-positive (HIV+) individuals commonly develop unexplained reductions in pulmonary diffusing capacity (DLCO). The potential relevance of this observation is underscored by recent data demonstrating that reductions in DLCO independently predict the subsequent development of opportunistic pneumonia. To delineate the alterations in gas exchange associated with HIV, we investigated a group of HIV+ subjects with unexplained reductions in DLCO, using high-resolution computed tomography (HRCT) of the chest and a separation of diffusing capacity into its membrane (Dm) and capillary blood volume (Vc) components. We compared this abnormal group with HIV+ subjects with more normal gas exchange and also with a group of HIV- volunteers matched for age and smoking history. Compared with other groups, the HIV+ group with diffusion impairment demonstrated prominent reductions in Vc, despite a well-preserved total lung capacity (TLC). HRCT demonstrated virtually no evidence of interstitial fibrosis in any HIV+ subject, but evidence of early emphysema that significantly correlated with DLCO. Our results suggest that the previously reported impairment in pulmonary gas exchange in the HIV+ population involves loss of Vc and likely represents the development of early emphysema.

HIV-positive individuals commonly have symptoms of airway disease. We evaluated thin-section CT scans of HIV-infected individuals during inspiration and expiration for evidence of focal air trapping. We also correlated imaging findings with pulmonary function test results.Fifty-nine subjects, 48 of whom were HIV-positive and 11 of whom were HIV-negative, underwent thin-section CT of the thorax during inspiration and expiration. All subjects also underwent pulmonary function tests. Two radiologists, who were unaware of the subjects' HIV status and smoking history and of the results of pulmonary function tests, evaluated the CT scans for the presence and severity of focal air trapping.Expiratory CT revealed focal air trapping in 33 subjects: 30 were HIV-positive and three were HIV-negative (p = .0338). The mean values of forced expiratory volume in 1 sec (FEV1), forced mid expiratory flow, and diffusion capacity (DL(CO)) were significantly lower for subjects with focal air trapping (mean = 88.85, 84.52, and 80.80, respectively) than for those with normal findings on CT (mean = 100.84, 99.24, and 95.82, respectively; p = .001, p = .021, and p = .003, respectively). We found no significant differences in smoking history between HIV-positive and HIV-negative subjects. Severe air trapping on expiratory CT scans was seen in three subjects: All three had HIV infection, low CD4 counts, and abnormally decreased FEV1 and DL(CO) values.Focal air trapping was a common finding on thoracic CT scans obtained during expiration in HIV-positive subjects. In addition, focal air trapping was associated with significantly lower FEV1, forced mid expiratory flow, and DL(CO) values than those found for subjects in whom CT revealed no focal air trapping. These results suggest that small airways disease may accompany a decline in pulmonary function in HIV-positive individuals.

Lung lymphocyte numbers are frequently increased in human immunodeficiency virus (HIV)-infected individuals in the absence of lung infection, and may play a critical role in viral surveillance and protection against new infections. In this context, cigarette smoking by HIV-infected individuals has been associated with a relative increase in the peripheral blood CD4(+) T-lymphocyte count as compared with that of nonsmokers. Because lung defense is local, the aim of the present study was to determine whether cigarette smoking had a significant impact on local lung defenses in HIV-infected individuals. The numbers and subtypes of bronchoalveolar lymphocytes and the ability of lung lavage cells to produce proinflammatory cytokines were compared in 58 smokers and 34 nonsmokers. In contrast to a trend toward an increase in peripheral blood CD4(+) cell counts among nonsmokers, smokers had significant depressions in both the percentage and absolute numbers of CD4(+) and CD8(+) cells in their bronchoalveolar lavage fluid (BALF). A decrease in CD4(+)/CD8(+) cell ratios was also seen with smoking. In addition, production of both interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) was suppressed with cigarette smoking. These observations show that cigarette smoking is associated with suppression in localized lung defenses, and suggest that smoking cessation may have a positive impact on lung defenses in HIV-infected smokers.

Although skeletal muscle abnormalities have been described in association with human immunodeficiency virus (HIV), the effects of HIV infection on respiratory muscle function have not been well characterized. We hypothesized that HIV+ individuals may develop respiratory muscle weakness and that respiratory muscle dysfunction may contribute to the unexplained dyspnea that occurs in the setting of HIV. To test this hypothesis we studied maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), inspiratory muscle endurance, and respiratory symptoms in 23 HIV+ male outpatients who had no history of acquired immune deficiency syndrome (AIDS)-related pulmonary complications, with a CD4+ T-lymphocyte count of 331.6 +/- 62.1 (mean +/- SEM). Respiratory muscle endurance was measured with an incremental threshold loading (ITL) protocol. We compared these results to those for 14 HIV- males matched for age and weight. Compared with the controls, HIV+ subjects had a significantly lower mean MIP (98.7 +/- 7.4 versus 121.4 +/- 9.3 cm H2O, p0.05) and MEP (115.0 +/- 9.3 versus 152.1 +/- 14.8 cm H2O, p0.05). Furthermore, during ITL, the mean load at task failure in the HIV+ group was 295.7 +/- 36.2 g, versus 405.8 +/- 52.2 g in the control group (p0.05). In the HIV+ subjects there was no relationship between muscle performance and CD4+ count or azidothymidine (AZT) use. There was, however, a highly significant relationship between respiratory muscle dysfunction and symptoms of dyspnea. We conclude that HIV seropositivity is associated with a decline in respiratory muscle performance. This impairment in respiratory muscle function may contribute to the feeling of breathlessness that has been well described in this patient population.

Author(s): Crothers, Kristina; McGinnis, Kathleen; Kleerup, Eric; Wongtrakool, Cherry; Hoo, Guy S; Kim, Joon; Sharafkhaneh, Amir; Huang, Laurence; Luo, Zhaoyu; Thompson, Bruce; Diaz, Philip; Kirk, Gregory D; Rom, William; Detels, Roger; Kingsley, Lawrence; Morris, Alison | Abstract: IntroductionPrior studies comparing abnormalities in pulmonary function between HIV-infected and HIV-uninfected persons in the current era are limited.ObjectivesTo determine the pattern and severity of impairment in pulmonary function in HIV-infected compared with HIV-uninfected individuals.MethodsCross-sectional analysis of 300 HIV-infected men and 289 HIV-uninfected men enrolled from 2009 to 2011 in 2 clinical centers of the Lung HIV Study. Participants completed pre- and postbronchodilator spirometry, diffusing capacity of the lung for carbon monoxide (DLCO) measurement, and standardized questionnaires.ResultsMost participants had normal airflow; 18% of HIV-infected and 16% of HIV-uninfected men had airflow obstruction. The mean percent predicted DLCO was 69% in HIV-infected vs. 76% in HIV-uninfected men (P l 0.001). A moderately to severely reduced DLCO of ≤60% was observed in 30% of HIV-infected compared with 18% of HIV-uninfected men (P l 0.001), despite the fact that 89% of those with HIV were on antiretroviral therapy. A reduced DLCO was significantly associated with HIV and CD4 cell count in linear regression adjusting for smoking and other confounders. The DLCO was lowest in HIV-infected men with CD4 cell counts l200 cells per microliter compared with those with CD4 cell counts ≥200 cells per microliter and to HIV-uninfected men. Respiratory symptoms of cough, phlegm and dyspnea were more prevalent in HIV-infected patients particularly those with abnormal pulmonary function compared with HIV-uninfected patients.ConclusionsHIV infection is an independent risk factor for reduced DLCO, particularly in individuals with a CD4 cell count below 200 cells per microliter. Abnormalities in pulmonary function among HIV-infected patients manifest clinically with increased respiratory symptoms. Mechanisms accounting for the reduced DLCO require further evaluation.

The spin trap N-tert-butyl-alpha-phenylnitrone (PBN) has a high avidity for free radical species and hence functions as an antioxidant in many biological systems. As such, we hypothesized that PBN would have powerful antioxidant effects on muscle function. We examined the effects of PBN on directly stimulated in vitro (37 degrees C) rat diaphragm. First, a dose-response curve for the effects of PBN on force frequency (n = 8) was established by comparing PBN-treated muscle strips (0.01-10 mM) with time- and stimulus-matched control strips. Second, the effect of 1.0 mM PBN on muscle endurance (n = 8) was established. Our findings were as follows. 1) Compared with baseline, peak twitch and low-frequency muscle tensions increased in a dose-dependent fashion, with peak effects at 1.0 mM PBN. 2) Muscle function at all stimulation frequencies was depressed at doses above 1.0 mM PBN. 3) Complete inhibition at 10 mM PBN was reversed with caffeine administration or washout. 4) During early fatigue, 1.0 mM PBN facilitated force. However, endurance time decreased in the PBN-treated group. We conclude that PBN has direct reversible dose-dependent effects on diaphragm function. However, facilitation of low-frequency forces and the lack of fatigue-attenuating properties suggest that PBN has atypical antioxidant effects on muscle function.