Authors: Ramsey Sabit; Dennis J. Shale

Author: Hans L. Rieder

Author: Elizabeth G. Nabel

Authors: MeiLan K. Han; Dirkje Postma; David M. Mannino; Nicholas D. Giardino; Sonia Buist; Jeffrey L. Curtis; Fernando J. Martinez

The prevalence of chronic obstructive pulmonary disease (COPD) in women is increasing, as is hospitalization for COPD. The number of women dying of COPD in the United States now surpasses men. Despite this, research suggests that physicians are still more likely to correctly diagnose men with COPD than women. Increased tobacco use in women likely explains some of the increase in the prevalence of COPD in women, but data suggest that women may actually be at greater risk of smoking-induced lung function impairment, more severe dyspnea, and poorer health status for the same level of tobacco exposure. The degree to which these observations represent biologic, physiologic, or sociologic differences is not known. Nonsmokers with COPD are also more likely to be female. In addition, new evidence is emerging that men and women may be phenotypically different in their response to tobacco smoke, with men being more prone to an emphysematous phenotype and women an airway predominant phenotype. Inasmuch as COPD is a disease of inflammation, it is also possible that sexual dimorphism of the human immune response may also be responsible for gender differences in the disease. More data are still needed on what the implications of these findings are on therapy. In this clinical commentary, we present current knowledge regarding how gender influences the epidemiology, diagnosis, and presentation of COPD in addition to physiologic and psychologic impairments and we attempt to offer insight into why these differences might exist and how this may influence therapeutic management.

Authors: Ian D. Pavord; Gerard Cox; Neil C. Thomson; Adalberto S. Rubin; Paul A. Corris; Robert M. Niven; Kian F. Chung; Michel Laviolette

Rationale: Bronchial thermoplasty (BT) is designed to reduce airway smooth muscle and improve asthma control.

Objectives: This study was conducted to determine the safety and efficacy of this procedure in subjects with symptomatic, severe asthma.

Methods: Adults who were symptomatic despite treatment with fluticasone or equivalent at more than 750 μg/day, a long-acting β2-agonist, and other medications, which could include 30 mg or less of oral prednisolone/day, were randomized to BT or to a control group. After treatment, subjects entered a 16-week steroid stable phase (Weeks 6–22), a 14-week steroid wean phase (Weeks 22–36), and a 16-week reduced steroid phase (Weeks 36–52).

Measurements and Main Results: BT resulted in a transient worsening of asthma symptoms. Seven hospitalizations for respiratory symptoms occurred in 4 of 15 BT subjects during the treatment period. Five hospitalizations were within 3 days of treatment. Two subjects had segmental collapse involving the most recently treated lobe; one required bronchoscopy and aspiration of a mucus plug. There were no hospitalizations during this period in the 17 control subjects. The rate of hospitalizations was similar in both groups in the post-treatment period. At 22 weeks, BT subjects had significant improvements versus control subjects in rescue medication use (−26.6 ± 40.1 vs. −1.5 ± 11.7 puffs/7 d, P < 0.05), prebronchodilator FEV1% predicted (14.9 ± 17.4 vs. −0.94 ± 22.3%, P = 0.04), and Asthma Control Questionnaire scores (−1.04 ± 1.03 vs. −0.13 ± 1.00, P = 0.02). Improvements in rescue medication use and Asthma Control Questionnaire scores remained significantly different from those of controls at 52 weeks.

Conclusions: BT is associated with a short-term increase in asthma-related morbidity. However, there is preliminary evidence of long-lasting improvement in asthma control.

Clinical trial registered with www.clinicaltrials.gov (NCT 00214539).

Authors: Muhammad T. Salam; W. James Gauderman; Rob McConnell; Pi-Chu Lin; Frank D. Gilliland

Rationale: Transforming growth factor (TGF)-β1 is involved in airway inflammation and remodeling, two key processes in asthma pathogenesis. Tobacco smoke and traffic emissions induce airway inflammation and modulate TGF-β1 gene expression. We hypothesized that the effects of functional TGF-β1 variants on asthma occurrence vary by these exposures.

Objectives: We tested these hypotheses among 3,023 children who participated in the Children's Health Study.

Methods: Tagging single-nucleotide polymorphisms rs4803457 C>T and C-509T (a functional promoter polymorphism) accounted for 94% of the haplotype diversity of the upstream region. Exposure to maternal smoking in utero was based on smoking by biological mother during pregnancy. Residential distance from nearest freeway was calculated based on residential address at study entry.

Measurements and Main Results: Children with the −509TT genotype had a 1.8-fold increased risk of early persistent asthma (95% confidence interval [CI], 1.11–2.95). This association varied marginally significantly by in utero exposure to maternal smoking. Compared with children with the −509CC/CT genotype with no in utero exposure to maternal smoking, those with the −509TT genotype with such exposure had a 3.4-fold increased risk of early persistent asthma (95% CI, 1.46–7.80; interaction, P = 0.11). The association between TGF-β1 C-509T and lifetime asthma varied by residential proximity to freeways (interaction P = 0.02). Children with the −509TT genotype living within 500 m of a freeway had over three-fold increased lifetime asthma risk (95% CI, 1.29–7.44) compared with children with CC/CT genotype living > 1500 m from a freeway.

Conclusions: Children with the TGF-β1 −509TT genotype are at increased risk of asthma when they are exposed to maternal smoking in utero or to traffic-related emissions.

Authors: R. Graham Barr; Sonia Mesia-Vela; John H. M. Austin; Robert C. Basner; Brad M. Keller; Anthony P. Reeves; Daichi Shimbo; Lori Stevenson

Rationale: Basic science research suggests a causal role for endothelial dysfunction in chronic obstructive pulmonary disease (COPD). Clinical studies examining endothelial function are lacking, particularly early in the disease. Flow-mediated dilation (FMD) is a physiologic measure of endothelial reactivity to endogenous nitric oxide.

Objectives: We hypothesized that lower FMD among former smokers would be associated with lower post-bronchodilator FEV1, higher percentage of emphysema using computed tomography (CT) and lower diffusing capacity.

Methods: We measured FMD, pulmonary function, and CT percentage of emphysema in a random sample of 107 cotinine-confirmed former smokers in the ongoing EMCAP study. FMD was defined as percentage change in the brachial artery diameter with reactive hyperemia. Generalized additive models were used to adjust for potential confounders and assess linearity.

Measurements and Main Results: Mean age of participants was 71 ± 5 years, 46% were female, and pack-years averaged 48 ± 26. Mean FMD was 3.8 ± 3.1%; mean post-bronchodilator FEV1, 2.3 ± 0.8 L; and mean CT percentage of emphysema, 26 ± 10%. A 1 SD decrease in FMD was associated with a 132-ml (95% confidence interval, 16–248 ml; P = 0.03) decrement in post-bronchodilator FEV1 and a 2.6% (95% confidence interval, 0.5–4.7%; P = 0.02) increase in CT percentage of emphysema in fully adjusted models. These associations were linear across the spectrum from normality to disease, independent of smoking history, and also significant among participants without COPD. Associations with diffusing capacity were consistent but nonsignificant (P = 0.09). The FMD–FEV1 association was entirely attributable to percentage of emphysema.

Conclusions: Impaired endothelial function, as measured by FMD, was associated with lower FEV1 and higher CT percentage of emphysema in former smokers early in COPD.

Authors: David A. McAllister; John D Maclay; Nicholas L. Mills; Grant Mair; Joy Miller; David Anderson; David E. Newby; John T. Murchison; William MacNee

Rationale: More patients with chronic obstructive pulmonary disease (COPD) die of cardiovascular causes than of respiratory causes, and patients with COPD have increased morbidity and mortality from stroke and coronary heart disease. Arterial stiffness independently predicts cardiovascular risk, is associated with atheromatous plaque burden, and is increased in patients with COPD compared with control subjects matched for cardiovascular risk factors. Elastin fragmentation and changes in collagen are found in the connective tissue of both emphysematous lungs and stiff arteries, but it is not known whether the severity of arterial stiffness in patients with COPD is associated with the severity of emphysema.

Objectives: To identify whether the extent of arterial stiffness is associated with emphysema severity.

Methods: We performed a cross-sectional study in 157 patients with COPD.

Measurements and Main Results: We measured pulse wave velocity (a validated measure of arterial stiffness), blood pressure, smoking pack-years, glucose, cholesterol, and C-reactive protein in 157 patients with COPD. We assessed emphysema using quantitative computed tomography scanning in a subgroup of 73 patients. We found that emphysema severity was associated with arterial stiffness (r = 0.471, P < 0.001). The association was independent of smoking, age, sex, FEV1% predicted, highly sensitive C-reactive protein and glucose concentrations, cholesterol–high-density lipoprotein ratio, and pulse oximetry oxygen saturations.

Conclusions: Emphysema severity is associated with arterial stiffness in patients with COPD. Similar pathophysiological processes may be involved in both lung and arterial tissue and further studies are now required to identify the mechanism underlying this newly described association.

Authors: David G. Parr; Peter G. Guest; John H. Reynolds; Lee J. Dowson; Robert A. Stockley

Rationale: α1-Antitrypsin (AAT) deficiency is associated with increased risk of chronic obstructive pulmonary disease (COPD), in particular emphysema, but airway disease is less well described.

Objectives: To assess the prevalence of airways disease in subjects with AAT deficiency and to identify the relationship between radiological airway abnormalities and clinical phenotype.

Methods: We characterized the computed tomographic phenotype of 74 subjects (PiZ), using visual scoring of airway disease and densitometric assessment of emphysema. Computed tomographic measurements were related to physiology, health status (St. George's Respiratory Questionnaire), and emphysema severity, and the relative impact of airway disease and emphysema severity on health status and airflow obstruction was compared by stepwise regression.

Measurements and Main Results: Bronchiectatic changes were seen in 70 subjects, and a subgroup with a bronchiectasis-predominant phenotype was identified. Clinically significant bronchiectasis (radiologic bronchiectasis in 4 or more bronchopulmonary segments together with symptoms of regular sputum production) occurred in 20 subjects (27%). AAT-deficient index cases had higher airway disease scores (P < 0.05), more severe emphysema (P < 0.001), and greater impairment of physiology (P < 0.001) and health status (P < 0.05) than nonindex cases. Airway disease scores correlated with health status, and bronchial wall thickening correlated with FEV1. Regression analysis indicated that emphysema severity had the strongest associations for health status (r = 0.505, P < 0.001) and FEV1 (r = 0.699, P < 0.001), but the addition of airway disease score improved the regression models (r = 0.596, P = 0.002 and r = 0.783, P < 0.001, respectively).

Conclusions: Emphysema is the predominant component of COPD in AAT deficiency, but the prevalence and impact of airway disease are greater than currently recognized. Consequently, future therapeutic strategies in AAT deficiency should also target this component of COPD.

Authors: Srinivas Papaiahgari; Adi Yerrapureddy; Swetha R. Reddy; Narsa M. Reddy; Jeffery M. Dodd-O; Michael T. Crow; Dimitry N. Grigoryev; Kathleen Barnes; Rubin M. Tuder; Masayuki Yamamoto; Thomas W. Kensler; Shyam Biswal; Wayne Mitzner; Paul M. Hassoun; Sekhar P. Reddy

Rationale: Mechanical ventilation (MV) is an indispensable therapy for critically ill patients with acute lung injury and the adult respiratory distress syndrome. However, the mechanisms by which conventional MV induces lung injury remain unclear.

Objectives: We hypothesized that disruption of the gene encoding Nrf2, a transcription factor that regulates the induction of several antioxidant enzymes, enhances susceptibility to ventilator-induced lung injury (VILI) and that antioxidant supplementation attenuates this effect.

Methods: To test our hypothesis and to examine the relevance of oxidative stress in VILI, we assessed lung injury and inflammatory responses in Nrf2-deficient (Nrf2^−/−) mice and wild-type (Nrf2^+/+) mice after an acute (2-h) injurious model of MV with or without administration of antioxidant.

Measurements and Main Results: Nrf2^−/− mice displayed greater levels of lung alveolar and vascular permeability and inflammatory responses to MV as compared with Nrf2^+/+ mice. Nrf2 deficiency enhances the levels of several proinflammatory cytokines implicated in the pathogenesis of VILI. We found diminished levels of critical antioxidant enzymes and redox imbalance by MV in the lungs of Nrf2^−/− mice; however, antioxidant supplementation to Nrf2^−/− mice remarkably attenuated VILI. When subjected to a clinically relevant prolong period of MV, Nrf2^−/− mice displayed greater levels of VILI than Nrf2^+/+ mice. Expression profiling revealed lack of induction of several VILI genes, stress response and solute carrier proteins, and phosphatases in Nrf2^−/− mice.

Conclusions: Our data demonstrate for the first time a critical role for Nrf2 in VILI, which confers protection against cellular responses induced by MV by modulating oxidative stress.

Authors: Fernando Holguin; Silvia Flores; Zev Ross; Marlene Cortez; Mario Molina; Luisa Molina; Carlos Rincon; Michael Jerrett; Kiros Berhane; Alfredo Granados; Isabelle Romieu

Rationale: Traffic-related emissions have been associated with respiratory symptoms in some studies. However, there is limited information on how traffic-related emissions relate to lung function and airway inflammation.

Objectives: To determine the differential association of traffic-related exposures with exhaled nitric oxide (NO) and lung volumes and symptoms in children with and without asthma.

Methods: We performed a longitudinal study of 200 children from ages 6 to 12 years of whom half had physician-diagnosed asthma. Two-week NO2 and 48-hour average levels of elemental carbon and particulate matter of less than 2.5 μm (PM2.5) were measured at participating schools. Road and traffic densities were determined at schools and at each participant's house.

Measurements and Main Results: In children with asthma, an interquartile increase in road density within the 50-, 100-, and 200-m home buffer areas was associated with increased exhaled NO (50 m: 28%; P = 0.03; 95% confidence interval [CI], 3–60; 100 m: 27%; P = 0.005; 95% CI, 8–49; 200 m: 17%, P = 0.09, 95% CI, −2 to 40), and reduced FEV1 (50 m: −0.091 L; P = 0.038; 95% CI, −0.174 to −0.007; 100 m: −0.072 L, P = −0.028, 95% CI, −0.134 to −0.009; 200 m: −0.106 L, P = 0.002, 95% CI, −0.171 to −0.041]). Exposure to NO2 at schools was marginally associated with reduced FEV1 (−0.020; P = 0.060; 95% CI, −0.042 to 0.001). We did not observe significant associations with PM2.5 or elemental carbon on exhaled NO. We did not observe significant reductions in lung volumes or changes in exhaled NO among healthy children.

Conclusions: Vehicular traffic exposures are associated with increased levels of exhaled NO and reduced lung volumes in children with asthma.

Authors: Momoyo Azuma; Yasuhiko Nishioka; Yoshinori Aono; Mami Inayama; Hideki Makino; Jun Kishi; Masayuki Shono; Katsuhiro Kinoshita; Hisanori Uehara; Fumitaka Ogushi; Keisuke Izumi; Saburo Sone

Rationale: Imatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-induced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect.

Objectives: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on α1-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance.

Methods: The concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing. The effects of AGP in vitro were evaluated by assaying the growth of lung fibroblasts. We examined the combined effects of erythromycin (EM) or clarithromycin (CAM) on bleomycin-induced pulmonary fibrosis in mice.

Measurements and Main Results: Addition of AGP abrogated imatinib-mediated inhibition of the growth of fibroblasts. However, treatment with EM or CAM restored the growth-inhibitory effects of imatinib. The elevated level of AGP was detected in serum and lung homogenates in bleomycin-exposed mice and reached a plateau on Day 14. Imatinib alone did not ameliorate pulmonary fibrosis when treatment was started on Day 15, whereas coadministration of imatinib and EM or CAM significantly reduced the fibrogenesis via inhibition of the growth of fibroblasts in vivo. Serum levels of AGP were higher in patients with idiopathic pulmonary fibrosis than in healthy subjects.

Conclusions: AGP is an important regulatory factor modulating the ability of imatinib to prevent pulmonary fibrosis in mice, and combined therapy with imatinib and EM or CAM might be useful for treatment of pulmonary fibrosis.

Authors: Hajime Fujimoto; Corina N. D'Alessandro-Gabazza; Moorthy S. S. Palanki; Paul E. Erdman; Takehiro Takagi; Esteban C. Gabazza; Nelson E. Bruno; Yutaka Yano; Tatsuya Hayashi; Shigenori Tamaki; Yasuhiro Sumida; Yukihiko Adachi; Koji Suzuki; Osamu Taguchi

Rationale: Cytokines secreted by T cells play a pivotal role in the pathogenesis of lung injury and fibrosis, and the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1 are involved in the expression of cytokines from T cells during lung injury.

Objectives: We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T-cell NF-κB and AP-1 in lung fibrosis.

Methods: The effect of SP100030 was evaluated using a mouse model of chronic lung fibrosis.

Measurements and Main Results: Mice treated with SP100030, as compared with untreated mice, had significantly less cachexia and less lung injury and had decreased levels of inflammatory cytokines and growth factors, decreased activation of coagulation activation, and decreased collagen deposition in the lung. The inhibitory activity of SP100030 was dose dependent and was effective in acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase Cθ-isoform in T-cell lines and suppressed NF-κB–driven cytokine expression in CD4⁺ and CD8⁺ T cells.

Conclusions: These results suggest that the specific inhibition of NF-κB could be useful for the treatment of lung fibrosis.

Authors: Anna Serrano-Mollar; Maria Nacher; Gemma Gay-Jordi; Daniel Closa; Antoni Xaubet; Oriol Bulbena

Rationale: Transplantation of stem cells has been proposed as a strategy for repair of lung fibrosis. Nevertheless, many studies have yielded controversial results that currently limit the potential use of these cells as an efficient treatment. Alveolar type II cells are the progenitor cells of the pulmonary epithelium and usually proliferate after epithelial cell injury. During lung fibrosis, however, the altered regeneration process leads to uncontrolled fibroblast proliferation.

Objectives: To investigate whether intratracheal transplantation of isolated alveolar type II cells can halt and reverse the fibrotic process in an experimental model of bleomycin-induced lung fibrosis in rats.

Methods: Lung fibrosis was induced in syngeneic female Lewis rats by a single intratracheal instillation of bleomycin (2.5 U/kg). Animals were transplanted with alveolar type II cells from male animals at a dose of 2.5 × 10⁶ cells per animal 3, 7, and 15 days after endotracheal bleomycin instillation. Animals were killed 21 days after the induction of lung fibrosis.

Measurements and Main Results: Lung fibrosis was assessed by histologic study and determination of hydroxyproline content. Engraftment of transplanted cells was measured by real-time polymerase chain reaction for the Y chromosome and by fluorescence in situ hybridization for the Y chromosome. Transplantation of alveolar type II cells into damaged lung 3, 7, or 15 days after bleomycin instillation led to reduced collagen deposition, and reduction in the severity of pulmonary fibrosis.

Conclusions: This study demonstrates the potential role of alveolar type II cell transplantation in designing future therapies for lung fibrosis.

Authors: Luciana Friedrich; Paulo M. C. Pitrez; Renato T. Stein; Marcelo Goldani; Robert Tepper; Marcus H. Jones

Rationale: It remains unclear whether premature birth, in the absence of neonatal respiratory disease, results in abnormal growth and development of the lung. We previously reported that a group of healthy infants born at 32–34 weeks' gestation and without respiratory complications had decreased forced expiratory flows and normal forced vital capacities at 2 months of age.

Objectives: Our current study evaluated whether these healthy infants born prematurely exhibited improvement or “catch-up” in their lung function during the second year of life.

Methods: Longitudinal measurements of forced expiratory flows by the raised volume rapid thoracic compression technique were obtained in the first and the second years of life for infants born prematurely at 32.7 (range, 30–34) weeks' gestation (n = 26) and infants born at full term (n = 24).

Measurements and Main Results: Healthy infants born prematurely demonstrate decreased forced expiratory flows and normal forced vital capacities in the first and second years of life. In addition, the increases in lung function with growth were similar to full-term infants.

Conclusions: Persistently reduced flows in the presence of normal forced vital capacity and the absence of catch-up growth in airway function suggest that premature birth is associated with altered lung development.

Authors: Nikolaus J. Buchner; Bernd M. Sanner; Jan Borgel; Lars C. Rump

Rationale: Obstructive sleep apnea (OSA) is linked to increased cardiovascular risk, but the impact of mild forms of OSA and their treatment on cardiovascular outcomes remains controversial.

Objectives: To prospectively investigate cardiovascular outcomes in treated versus untreated patients with OSA.

Methods: Consecutive sleep laboratory patients with all degrees of OSA were included. Endpoints were nonfatal (myocardial infarction, stroke, and acute coronary syndrome requiring revascularization procedures) and fatal (death from myocardial infarction or stroke) cardiovascular events.

Measurements and Main Results: Comparison of event-free survival rates in treated versus untreated patients (Kaplan-Meier estimates, log-rank test). Of 449 patients enrolled (age, 56.0 ± 10.5 years; body mass index, 30.8 ± 5.4 kg/m²), 364 patients received OSA treatment, and 85 patients remained untreated. Median follow-up was 72.0 months (range, 1–156). Mean apnea–hypopnea index before treatment was 30.9 ± 21.8/hour in treated and 15.3 ± 13.0/hour in untreated patients, but there were no differences in cardiovascular comorbidities or risk factors. In patients with mild–moderate OSA (n = 288), events were more frequent in untreated patients (estimated event-free survival at 10 yr, 51.8 vs. 80.3% [P < 0.001]; absolute risk reduction, 28.5%; number needed to treat to prevent one event/10 yr, 3.5). After adjustment for age, gender, cardiovascular risk factors, and comorbidities at baseline, OSA treatment was an independent predictor for events (hazard ratio, 0.36; 95% confidence interval, 0.21–0.62; P < 0.001).

Conclusions: OSA treatment was associated with a cardiovascular risk reduction of 64% independent from age and preexisting cardiovascular comorbidities. OSA treatment should be considered for primary and secondary cardiovascular prevention, even in milder OSA.

Authors: Ellen A. van der Eijk; Esther van de Vosse; Jan P. Vandenbroucke; Jaap T. van Dissel

Rationale: In his 1978 article on tuberculosis (TB) in twins, Comstock concluded that the 2.5-fold higher concordance rate for TB among monozygotic versus dizygotic twins in the Prophit survey of the 1950s implicated inherited susceptibility as a major risk factor for TB in humans. His analysis did not take into account strong imbalance of variables within subgroups, underestimating possible confounding effects of environmental factors.

Objectives: To reconsider the role of environmental versus hereditary factors in determining the concordance rate of TB among twin pairs.

Methods: Reanalysis of the Prophit Survey.

Measurements and Main Results: A known Mycobacterium tuberculosis–positive or M. tuberculosis–negative sputum in the index TB case markedly influenced the odds ratio (OR) of concordance in the twin pairs. In 87 pairs with co-twins exposed to a sputum-negative index case, monozygotic and dizygotic twins did not differ in concordance for TB (OR, 1.1; 95% confidence interval [95% CI], 0.4–2.8). A higher concordance rate for TB among monozygotic versus dizygotic twins was confined to 106 pairs with the co-twins exposed to a sputum-positive index case (OR, 3.4; 95% CI, 1.6–7.2), and was highest in adolescent twins living together. ORs of TB concordance were proportional to intensity of exposure (sputum smear positivity, physical proximity between twin pairs, contagiousness of disease, and living together) rather than to zygosity.

Conclusions: In the Prophit survey of susceptibility to TB among twins, environmental factors (i.e., intensity of exposure to tubercle bacilli) outweigh the importance of hereditary factors. Environmental factors and the context of transmission should be given more emphasis when studying interindividual and population differences in susceptibility to infectious diseases such as TB.

Authors: Eyal Robenshtok; Mical Paul; Leonard Leibovici

Authors: Forest W. Arnold; James T. Summersgill; Andrew S. LaJoie; Paula Peyrani; Thomas J. Marrie; Paolo Rossi; Francesco Blasi; Patricia Fernandez; Thomas M. File; Jordi Rello; Rosario Menendez; Carlos M. Luna; Julio A. Ramirez