Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Tr

     Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois

    CONTENTS

    TOP

    CONTENTS

    CHRONIC OBSTRUCTIVE PULMONARY...

    AIR POLLUTION

    PULMONARY VASCULAR DISORDERS AND...

    LUNG TRANSPLANTATION

    PLEURAL DISORDERS

    LUNG CANCER

    REFERENCES

    Chronic Obstructive Pulmonary Disease (49)

    Genetics (1)

    Epidemiology (3)₁¨CAntrypsin Deficiency (2)

    Risk Factors (1)

    Cellular, Molecular, and Anatomical Abnormalities (10)

    Lung Inflammation (1)

    Pathophysiologic and Radiologic Studies (2)

    Pulmonary Vasculature (1)

    Control of Breathing and Exercise (2)

    Respiratory Muscles (3)

    Peripheral Muscles (5)

    Drug Therapy (13)

    Muscarinic Antagonists (1)

    Theophylline (2)

    Glucocorticoids (7)

    Experimental Protease Inhibitors (3)

    Other Therapies (3)

    Lung Volume Reduction Surgery (2)₁-Antitrypsin Replacement Therapy (1)

    Outcome (1)

    Workshops (1)

    Air Pollution (6)

    Air Pollution¡ªGeneral (5)

    Diesel Exhaust (1)

    Pulmonary Vascular Disorders and Related Disorders (17)

    Pulmonary Hypertension (13)

    Molecular and Pathophysiologic Mechanisms (6)

    Treatment (7)

    Thromboembolic Disorders (1)

    Diagnostic Studies (1)

    High Altitude (2)

    Sickle Cell Disease (1)

    Lung Transplantation (13)

    Lung Preservation (3)

    Patient Selection (3)

    Obliterative Bronchiolitis (5)

    Animal Models (3)

    Early Detection (2)

    Rejection (1)

    Immunology and Biochemistry (1)

    Pleural Disorders (7)

    Physiology/Pathophysiology (3)

    Clinical Manifestations (1)

    Treatment (2)

    Pleurodesis (1)

    Lung Cancer (6)

    Diagnosis (4)

    Studies of Molecular Mechanisms (1)

    Review Article (1)

    CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    TOP

    CONTENTS

    CHRONIC OBSTRUCTIVE PULMONARY...

    AIR POLLUTION

    PULMONARY VASCULAR DISORDERS AND...

    LUNG TRANSPLANTATION

    PLEURAL DISORDERS

    LUNG CANCER

    REFERENCES

    Genetics

    Because oxidative stress is believed to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD), He and coworkers (1) studied the relationship between polymorphisms of antioxidant genes and susceptibility to accelerated decline of lung function in smokers. Of 594 white smokers in the Lung Health Study, 286 experienced a rapid decline in FEV₁ (-152 ml per year) and 308 did not show a decline (+15 ml per year). None of the genotypes¡ªglutathione S-transferase (GST) M1, T1, P1, or heme oxygenase-1¡ªhad an individual effect on decline in lung function. Rapid decline in lung function was associated with the presence of all three GST polymorphisms (odds ratio, 2.83). A combination of family history of COPD with GSTP1 105IIe/IIe genotype was associated with rapid decline in lung function (odds ratio, 2.2). The authors conclude that decline of lung function in smokers is not associated with any of the genotypes for glutathione S-transferase or hemeoxygenase-1.

    Epidemiology

    In the GOLD (Global Initiative For Chronic Obstructive Lung Disease) guidelines, Stage 0 includes subjects without airway obstruction (FEV₁/FVC greater than 0.70) who have respiratory symptoms (productive cough). Subjects with GOLD Stage 0 are considered at increased risk for COPD. To assess the usefulness of Stage 0, Vestbo and Lange (2) analyzed data on more than 10,000 participants in the Copenhagen City Heart Study. Criteria for GOLD Stage 0 were fulfilled by 5.8% of the total population and by 7.2% of smokers at baseline. At 5 years of follow-up, 13.2% of smokers with GOLD Stage 0 had developed a decrease in FEV₁/FVC to less than 0.7; this change occurred in 11.6% of smokers without respiratory symptoms. At 15 years of follow-up, a decrease in FEV₁/FVC to less than 0.7 occurred in 20.5% of smokers with GOLD Stage 0 and in 18.5% of smokers without respiratory symptoms. Multivariate logistic regression analysis revealed that GOLD Stage 0 did not identify subsequent airway obstruction. The authors conclude that GOLD Stage 0 is of little help in identifying subjects at risk of COPD and that cigarette smoking itself remains the best predictor of risk.

    Eleven years after the Lung Health Study, Anthonisen and coworkers (3) did spirometry on 77% of the surviving participants. Smoking habits tended to converge; 93% of those who abstained from smoking during the study were still abstinent at 11 years. Men who quit smoking at the beginning of the study had a decline in FEV₁ of 30 ml per year, as compared with a decline of 66 ml per year in men continuing to smoke throughout the 11 years. Women who quit smoking at the beginning of the study had a decline in FEV₁ of 22 ml per year, as compared with a decline of 54 ml per year in women continuing to smoke throughout the 11 years. When expressed as a percentage of predicted normal value, the decline in FEV₁ in male and female smokers was equivalent. At 11 years, 38% of individuals who continued to smoke had an FEV₁ of less than 60% of the predicted normal value, as compared with 10% in the individuals who stopped smoking permanently. The authors conclude that the loss of lung function among continuing smokers is more rapid than previously suspected.

    To determine whether measures of quality of life are associated with increased mortality, Domingo-Salvany and coworkers (4) analyzed data on a cohort of 321 men with COPD 5 to 6 years after enrollment. One third of the patients had died. Compared with survivors, the patients who died were older (70 versus 63 years), had lower body mass index (25 versus 27), lower FEV₁ (34 versus 51% predicted), and made more frequent use of long-term oxygen therapy (31 versus 7%). After adjusting for relevant clinical and physiologic variables, both the total St. George¡¯s Respiratory Questionnaire and the physical summary score of SF-36 were independently associated with both all-cause mortality and respiratory mortality. The total mortality hazard ratio was 1.3 for the two measures of quality of life, and 1.6 for FEV₁. The authors conclude that measures of quality of life provide independent information on the health status of men with COPD and are independently associated with mortality.

    ₁-Antrypsin Deficiency

    Rodriguez and coworkers (5) describe a new method of screening for ₁-antitrypsin deficiency. The technique employs dried blood spots and a LightCycler fluorimetric analyzer. Among 72 patients with COPD, 22% had neither PiZ nor PiS mutations, 7% were non-S, non-Z heterozygotes, 35% were heterozygotes who had a PiZ plus a non-S, non-Z allele, 3% had the PiSS genotype, 3% were PiSZ, and 28% were PiZZ. All patients with two normal alleles and 10 heterozygous carries had normal levels of ₁-antitrypsin. Processing of 32 samples took only 40 minutes. The authors conclude that fluorimetric analysis of dried blood specimens is suitable for large-scale screening for ₁-antitrypsin deficiency.

    Takubo and coworkers (6) determined whether the level of ₁-antitrypsin influenced the pattern of emphysema induced by cigarette smoke in mice. Exposure to cigarette smoke for four months produced emphysema (an increase in the mean linear intercept) in pallid mice that have a low level of ₁-antitrypsin but not in C57 mice. After six months of smoke exposure, the degree of emphysema was equivalent in the two groups of mice. The pallid mice developed more diffuse emphysema than did the C57 mice. T cell inflammation was present in the alveolar walls of the pallid mice, but not in the C57 mice after 6 months of smoking. Lung compliance increased over the 6 months in the pallid mice but not in the C57 mice. The authors conclude that cigarette smoking produces emphysema in both pallid and C57 mice, and that the emphysema is panlobular in pallid mice that have low levels of ₁-antitrypsin, whereas it is centrilobular in C57 mice.

    Risk Factors

    Birring and coworkers (7) prospectively identified 25 patients with COPD who had never smoked or who had a smoking history of less than 5 pack-years. These patients represented 5.7% of total referrals with fixed airway obstruction over 2 years. The patients had a mean age of 70 years, were mainly women (86%), and had a mean duration of respiratory symptoms of 7 years. Mean FEV₁ was 58%, and the FEV₁/FVC ratio was 55%. Features on high-resolution computed tomography were typical of COPD. Sputum induction revealed eosinophilia in 9 patients and neutrophilia in 13 patients. Organ-specific autoimmune disease was present in 32% of patients, especially in the patients who did not display sputum eosinophilia (46% of patients). The authors conclude that the occurrence of COPD among nonsmokers is mainly seen in women and that some patients have features of organ-specific autoimmune disease.

    Cellular, Molecular, and Anatomic Abnormalities

    Some exacerbations of COPD are caused by infection with nontypeable Haemophilus influenzae. Abe and coworkers (8) determined whether the lymphocytes of patients experiencing frequent exacerbations have decreased ability to recognize P6 (P6 is a lipoprotein of the outer membrane that is highly conserved among strains of nontypeable H. influenzae). The in vitro lymphocyte proliferative response to P6 was 0.82 in 10 patients with COPD who had experienced an exacerbation caused by nontypeable H. influenzae in the preceding 12 months as compared with 1.42 in 26 patients with COPD who did not have such an exacerbation, and 1.61 in 12 healthy subjects. Serum antibody levels to P6 did not differ between the two groups of patients with COPD. The lymphocyte response to an unrelated antigen, tetanus toxoid, did not differ among the three groups. The authors conclude that a decrease in the proliferation of lymphocytes in response to P6 is associated with increase in the frequency of exacerbations of COPD.

    Smokers who develop COPD have bronchopulmonary inflammation, characterized by increased T lymphocytes. To determine whether patients with COPD have increased expression of CXCR3 (a chemokine receptor preferentially expressed on Type-1 T lymphocytes) and its ligand, CXCL10, Saetta and coworkers (9) studied airways of subjects undergoing lung resection for localized lesions. The numbers of CXCR3+ cells in the epithelium and submucosa of the peripheral airways of seven smokers with COPD was higher than in five smokers with normal lung function and in seven nonsmokers with normal lung function. The ligand of CXCR3, the interferon-induced protein CXCL10, was present in the bronchiolar epithelium of smokers with COPD but not in the bronchiolar epithelium of the other two groups. Most of the CXCR3 cells co-expressed CD8 and produced interferon-. The authors conclude that the T cells infiltrating the peripheral airways of smokers with COPD have increased expression of the chemokine receptor CXCR3 and a parallel increase in its ligand CXCL10.

    To characterize and qualify the inflammatory processes in the small airways of smokers with COPD, Turato and coworkers (10) studied surgical specimens from 9 patients with severe COPD (FEV₁, 29% predicted) and 9 patients with a similar smoking history who had mild or absent airway obstruction (FEV₁, 86% predicted). Compared with the smokers who had mild or absent airway obstruction, the smokers with severe COPD had increased numbers of leukocytes in the small airways. The leukocytes were positively correlated with the radiologic score of emphysema and residual volume, and were negatively correlated with FEV₁ and diffusing capacity. The inflammatory process was characterized by an increase in CD8⁺ and CD4⁺ T lymphocytes in the airway wall and an increase in macrophages in the airway epithelium. Taking all smokers together, smoking history was correlated with both the thickness of the airway wall and the thickness of smooth muscle. Structural and cellular findings in the pulmonary arteries did not differ between the two groups. The authors conclude that the small airways of smokers with severe COPD display an increased number of leukocytes, which is correlated with severity of airway obstruction, impaired diffusing capacity, hyperinflation, and radiologic emphysema.

    4-Hydroxy-2-nonenal is a highly diffusible product of lipid peroxidation and a key mediator of oxidant-induced cell signaling and apoptosis. To determine the role of this aldehyde in COPD, Rahman and coworkers (11) obtained surgical lung specimens from 23 current or ex-smokers, 11 of whom had COPD (FEV₁ less than 70% of predicted) and 12 of whom did not have COPD. 4-Hydroxy-2-nonenal¨Cmodified protein levels were higher in airway and alveolar epithelial cells, endothelial cells, and neutrophils of the patients with COPD than in the subjects without COPD. FEV₁ was correlated with the level of the aldehyde in bronchial endothelium (r = -0.61) and neutrophils (r = -0.56). Transforming growth factor-ß₁ was correlated with the level of the aldehyde in the bronchial epithelium (r = 0.62) and alveolar epithelium (r = 0.51). The authors conclude that the levels of 4-hydroxy-2-nonenal play a role in the signaling events of lung inflammation leading to an imbalance in the expression of both proinflammatory mediators and protective antioxidant genes in COPD.

    The increase in alveolar macrophages in cigarette smokers may result from increased recruitment, increased proliferation, or decreased cell death. To determine whether chronic cigarette smoke influences the expression and localization of cell-cycle and apoptotic proteins in alveolar macrophages and bronchial epithelial cells, Tomita and coworkers (12) obtained bronchial biopsies from 10 healthy smokers, 7 patients with mild to moderate asthma, and 6 control subjects. The increased numbers of alveolar macrophages in the smokers resulted only in part from increased proliferation. Expression of p21^CIP1/WAF1, a key protein that regulates the cell cycle and is responsive to oxidative stress, was increased in the alveolar macrophages and in bronchial biopsies from the smokers; it was found predominantly within the cytoplasm. Compared with the control subjects and patients with asthma, B cell lymphoma leukemia (Bcl)-x_L, an antiapopoptotic regulator, was highly expressed in macrophages from the smokers. In in vitro studies, hydrogen peroxide induced cytoplasmic expression of p21^CIP1/WAF1 and failed to induce apoptosis. The authors conclude that p21^CIP1/WAF1 and B cell lymphoma leukemia proteins are increased in alveolar macrophages of cigarette smokers and that the increase in macrophages in smokers appears to result from inhibition of apoptosis. An editorial commentary by Vignola (13) accompanies this article.

    The rate-limiting enzyme in the production of glutathione is -glutamylcysteine synthetase, which is downregulated by oxidant exposure. Harju and coworkers (14) studied the localization of the enzyme in 22 patients with COPD, 20 smokers without COPD, and 13 nonsmokers. Both the heavy and light subunits of -glutamylcysteine synthetase were expressed most prominently in the large airways and localized in the cytoplasm and along the plasma membrane. The heavy subunit was more heavily expressed in the central bronchial epithelium than in peripheral bronchioli or in alveolar macrophages. Alveolar macrophages of nonsmokers had higher levels of both subunits than did macrophages of smokers. Expression of the heavy subunit in the central bronchial epithelium was greater in nonsmokers than in patients with COPD; the smokers and patients with COPD did not differ. The authors conclude that heavy and light subunits of -glutamylcysteine are expressed mainly in the large airways, and that their lower concentration in smokers may contribute to progression of oxidant-induced lung injury. An editorial commentary by Hiemstra (15) accompanies this article.

    Lung tissue from patients with emphysema carries an excess of adenoviral E1A DNA, which is expressed as a protein in the airway surface epithelium and associated with an increased inflammatory response. To investigate the mechanisms whereby the latent adenoviral infection amplifies the inflammatory process, Higashimoto and coworkers (16) obtained lung tissue from three patients undergoing lung resection, and transfected cultures of bronchial epithelial cells with a plasmid containing the adenovirus 5 E1A gene. When stimulated by lipopolysaccharide, the transfected epithelial cells increased intercellular adhesion molecule-1, and interleukin-8 messenger RNA and protein expression. Lipopolysaccharide also induced greater activity of intercellular adhesion molecule-1 promoter and greater binding activity of nuclear factor-B in nuclear extracts of the transfected cells. The transfected cells displayed constitutive expression of messenger RNA and protein for transforming growth factor-ß1. The authors conclude that transfection of human bronchial epithelial cells with adenovirus E1A DNA upregulates the production of mediators that are involved in the pathogenesis of emphysema.

    To better define the role of tumor necrosis factor- as a mediator of lung damaged caused by cigarette smoking, Churg and coworkers (17) studied three groups of mice. In control mice, cigarette smoke caused increases in gene expression for tumor necrosis factor-, macrophage inflammatory protein-2, and macrophage chemoattractant protein-1; these changes returned to control values by 6 hours. Exposure of knockout mice that lacked the p55/p75 receptors for tumor necrosis factor- showed no change in the gene expression of these mediators at any time. At 24 hours, the control mice, but not the knockout mice, displayed an increase in lavage neutrophils, macrophages, desmosine (a measurement of elastin breakdown), and hydroxyproline (a measure of collagen breakdown). Exposure of pure strain 129 mice (mice that produce only low levels of tumor necrosis factor-) to cigarette smoke produced no inflammatory response at 24 hours or at 7 days. The authors conclude that tumor necrosis factor- is central to smoke-induced inflammation and tissue breakdown.

    Lung Inflammation

    To determine the relationship between local and systemic inflammatory mediators in patients with COPD, Vernooy and coworkers (18) obtained plasma and sputum from 18 patients with COPD (FEV₁, 56% predicted) and 17 healthy smokers (FEV₁, 99% predicted). Compared with the control group, induced sputum from the patients revealed a higher percentage of neutrophils (81 versus 62%), and higher levels of interleukin-8 (3.7 versus 2.3 pg per ml) and soluble tumor necrosis factor-receptor 55 (237 versus 109 pg per ml). The level of tumor necrosis factor- in induced sputum was equivalent in the two groups. In plasma, the patients had a higher level of soluble tumor necrosis factor-receptor 75 than did the control group (1.9 versus 1.4 ng per ml). The levels of inflammatory mediators in plasma and induced sputum were not correlated with each other. In the patients, FEV₁ was correlated with the sputum levels of interleukin-8 (r = -0.84) and soluble tumor necrosis factor-receptor 55 (r = -0.52). The levels of interleukin-8, soluble tumor necrosis factor-receptor 55, and soluble tumor necrosis factor-receptor 57 were higher in the sputum of patients with COPD who were ex-smokers than in patients who were current smokers. The authors conclude that sputum levels of neutrophils, interleukin-8, and soluble tumor necrosis factor-receptor 55 are higher in patients with COPD than in healthy smokers, and that the levels of inflammatory mediators in sputum do not correlate with the levels in plasma.

    Pathophysiologic and Radiologic Studies

    Brown and coworkers (19) compared the deposition and clearance of ultrafine technetium-99m¨Clabeled aerosol in 10 patients with COPD (FEV₁, 54% predicted) and 9 healthy subjects. For an aerosol exposure of 10 µg per m³, the dose rate was greater in the patients than in the control subjects (2.9 versus 1.9 µg per hour). The central-to-peripheral index, a measure of airway deposition, was greater in the patients than in the control subjects (1.11 versus 1.01). Clearance did not differ between the patients and the control group, and the average 24-hour retention was 85%. Particles were not seen to accumulate in the liver. The authors conclude that the deposition of ultrafine particles is greater in patients with COPD than in healthy subjects.

    Because more women than men attend specialist cough clinics, Kastelik and coworkers (20) compared the sensitivity of the cough reflex in 60 female and 50 male patients with chronic cough. The dose of inhaled capsaicin inducing two coughs was 2.2 times smaller and the dose inducing five coughs was 6 times smaller in the women than in the men. The dose of inhaled citric acid inducing cough was 2.2 times smaller and the dose inducing five coughs was 2.8 times smaller in the women than in the men. The authors conclude that female patients with chronic cough displayed greater sensitivity to cough than do male patients.

    Pulmonary Vasculature

    To characterize the hemodynamic abnormalities in patients with severe emphysema, Scharf and coworkers (21) studied 120 patients participating in the National Emphysema Treatment Trial. The patients had an FEV₁ of 27% of predicted and a residual volume of 225% of predicted; 91% of the patients had a mean pulmonary artery pressure at end-expiration of greater than 20 mm Hg, and 61% had a wedge pressure at end-expiration of greater than 12 mm Hg. Cardiac index was normal. The mean pulmonary artery pressure correlated inversely with PO₂ and with severity of emphysema, and directly with the wedge pressure. On multiple stepwise regression, PO₂ was not an independent predictor of mean pulmonary artery pressure. Diastolic ventricular pressures were increased without evidence of systolic dysfunction. The authors conclude that patients with severe emphysema commonly display elevated pulmonary vascular pressures, that increase in pulmonary artery pressure is not related to hypoxemia, that pulmonary hypertension is not associated with impaired systemic oxygen transport, and that high cardiac diastolic pressures do not represent systolic dysfunction.

    Control of Breathing and Exercise

    To determine factors that lead to an increase in PCO₂ during exercise, O¡¯Donnell and coworkers (22) studied 20 patients with COPD (FEV₁, 34% of predicted). During maximum cycle exercise, patients increased PCO₂ by 7 mm Hg (range, -6 to 25 mm Hg). The change in PCO₂ from rest to exercise was best correlated with the change in PCO₂ while breathing 60% oxygen (an indirect test of ventilation¨Cperfusion mismatching; r² = 0.62) and with resting oxygen saturation (r² = 0.30). Serial changes in PCO₂ during exercise were most closely correlated with changes in end-expiratory lung volume (r = 0.56) and oxygen saturation (r = 0.82). The authors conclude that the development of hypercapnia during exercise in patients with COPD is related to the development of dynamic hyperinflation and abnormalities of ventilation¨Cperfusion matching. An editorial commentary by Dempsey (23) accompanies this article.

    Respiratory Muscles

    Ramirez-Sarmiento and coworkers (24) studied the effect of inspiratory muscle training on the structure of the inspiratory muscles in patients with COPD. Fourteen men (FEV₁, 24% predicted) were randomized to true training or sham training. Training consisted of breathing through an inspiratory threshold device while generating 40 to 50% of maximum inspiratory pressure. The training was supervised and the sessions consisted of 30 minutes a day, 5 times a week, for 5 consecutive weeks. Training produced a 29% increase in maximal inspiratory pressure and 100% increase in inspiratory muscle endurance (the length of time that a patient was able to breathe against a load requiring the generation of 80% of maximal inspiratory pressure). Biopsies from the external intercostal muscles before and after training revealed a 38% increase in the proportion of type I fibers and a 21% increase in the size of type II fibers. Training had no effect on the structure of the vastus lateralis. The authors conclude that the improvement in inspiratory muscle strength and endurance after five weeks of supervised inspiratory muscle training is accompanied by increases in the proportion of type I fibers and the size of type II fibers. An editorial commentary by Levine and colleagues (25) accompanies this article.

    It has been generally believed that shortening of the diaphragm in hyperinflated patients with COPD is accompanied by a decrease in the contribution of the diaphragm to tidal breathing. Gorman and coworkers (26) used ultrasonography and magnetometry to measure diaphragmatic length at different lung volumes in 10 men with COPD (FEV₁, 23% of predicted) and 10 control subjects. The length of the diaphragm was 20% shorter in the patients at residual volume and functional residual capacity, but length was similar to that of the control subjects at total lung capacity. The length of the zone of apposition was decreased by 50% at residual volume and functional residual capacity in the patients. At a given absolute lung volume, however, the length of the zone of apposition was greater in the patients. Although mean functional residual capacity was equivalent to predicted total lung capacity in the patients, tidal volume, tidal changes in the length of the zone of apposition and length of the diaphragm, and tidal volume displaced by the diaphragm were equivalent in the patients and in the control subjects. The authors conclude that, despite shortening of the diaphragm in patients with COPD, the motion and change in length of the diaphragm during tidal breathing is equivalent in patients with COPD and healthy subjects.

    Peripheral Muscles

    To determine the role of apoptosis of skeletal muscle in causing weight loss in patients with COPD, Agusti and coworkers (27) obtained biopsies from the quadriceps femoris in 7 patients with COPD who had a low body mass index (less than 20 kg per m²), 8 patients with COPD who had a normal body weight, 8 healthy volunteers, and 6 subjects requiring orthopedic surgery (to assess effects of inactivity). The percentage of cells positive for TUNEL (transferase-mediated dUTP nick and labeling) was 57% in patients with COPD and low body weight, 17% in patients with COPD and normal body weight, 6% in the orthopedic patients, and 4% in healthy subjects. A similar pattern was seen with another marker of apoptosis: the immunodetection of poly-(ADP-ribose)-polymerase proteolytic fragments (PARP). In the patients with COPD, body mass index was inversely related to apoptosis, as measured by TUNEL (r = -0.65). Body mass index was also related to peak oxygen consumption during exercise (r = 0.74) and to FEV₁ (r = 0.66). Markers of skeletal muscle apoptosis were not related to any variables of lung function. The authors conclude that apoptosis of skeletal muscle is increased in patients with COPD who have a low body mass index and is associated with impaired exercise tolerance independently of the effect on lung function. An editorial commentary by Lewis (28) accompanies this article.

    To compare the relative efficacy of strength versus endurance training, Ortega and coworkers (29) studied 47 patients with COPD. Strength training consisted of a series of weight-lifting exercises, and endurance training consisted of leg exercises on an ergocycle at 70% of peak work rate. Improvements in dyspnea and quality of life were still evident at three months after completing the training program. Compared with patients undergoing strength training alone, improvements in submaximal exercise capacity were greater in patients undergoing either endurance training or the combination of endurance training and strength training. Increases in the strength of muscle groups (chest pull, neck press, leg flexion and extension) were equivalent in patients undergoing strength training alone and patients undergoing the combination of strength training plus endurance training: the increases in strength in both of these groups was higher than in patients undergoing endurance training alone. Increase in walking distance was restricted to the group undergoing strength training. The authors conclude that a combination of strength training plus endurance training achieves maximal muscle training in patients with COPD.

    To determine whether muscle mass is a better predictor of survival than is body mass index, Marquis and coworkers (30) followed 142 patients with COPD (FEV₁, 42% of predicted) for an average of 41 months. Only the cross-sectional area of midthigh muscle (obtained by computed tomography) and FEV₁ were significant predictors of mortality. Mortality was not related to body mass index, thigh circumference, age, sex, daily use of glucocorticoids, diffusing capacity, PO₂, PCO₂, or peak work rate during exercise. Compared with the patients who had an FEV₁ of at least 50% of predicted plus a midthigh muscle area of at least 70 cm², the patients who had an FEV₁ of less than 50% of predicted and a muscle area of at least 70 cm² had a mortality odds ratio of 3.37. Compared with the patients who had an FEV₁ of at least 50% of predicted plus a midthigh muscle area of at least 70 cm², the patients who had an FEV₁ of less than 50% of predicted and muscle area of less than 70 cm² had a mortality odds ratio of 13.16. Anthropometric measurements could not predict midthigh muscle area. The authors conclude that midthigh cross-sectional muscle area is a better predictor of mortality in patients with COPD than is body mass index. An editorial commentary by Mador (31) accompanies this article.

    Drug Therapy

    Muscarinic antagonists.

    The Lung Health Study involved 5,887 smokers who did not regard themselves as ill but who had mild to moderate impairment of lung function. Anthonisen and coworkers (32) analyzed the data to assess factors influencing morbidity and mortality. Over 5 years, 149 (2.5%) participants died, largely from lung cancer and cardiovascular disease. A total of 12.8% of participants were hospitalized: 75% of hospitalizations resulted from cancer, cardiovascular disease, and nonmalignant respiratory disease. Death and hospitalizations for cardiovascular disease and coronary artery disease tended to be more common in individuals assigned to the smoking intervention plus ipratropium bromide arm of the study than among individuals in the smoking intervention plus placebo arm (the difference approached statistical significance). Nine individuals in the smoking intervention plus ipratropium arm were hospitalized for supraventricular tachycardia as compared with two individuals in the smoking intervention plus placebo arm. The authors conclude that use of ipratropium bromide was associated with an increased tendency for cardiovascular disease and supraventricular tachycardia.

    Theophylline.

    Culpitt and coworkers (33) asked, "Does theophylline decrease airway inflammation in patients with COPD?" In a double-blind randomized trial, 25 patients with COPD were treated with low-dose theophylline (plasma level 9 to 11 mg per liter) for 4 weeks. Theophylline produced decreases of about 22% in induced sputum inflammatory cells, neutrophils, interleukin-8, myeloperoxidase, and lactoferrin. Neutrophils from subjects treated with theophylline displayed a decrease in chemotaxis to N-formyl-met-leu-phe of about 28% and to interleukin-8 of about 60%. Theophylline produced a 34% decrease in the chemotaxis of healthy donor neutrophils to induced sputum. The authors conclude that administration of theophylline to patients with COPD produces a decrease in sputum neutrophils, sputum chemotactic activity, and chemotaxis of peripheral blood neutrophils to chemotactic stimuli. An editorial commentary by Rabe (34) accompanies this article.

    Glucocorticoids.

    In 199 patients with an acute exacerbation of COPD, Maltais and coworkers (35) did a double-blind randomized trial of nebulized budesonide (2 mg every 6 hours), oral prednisolone (30 mg every 12 hours), and placebo. Compared with placebo, the postbronchodilator FEV₁ was 0.10 liter higher with budesonide and 0.16 liter higher with prednisolone; the difference between budesonide and prednisolone was not significant. Adverse effects were equivalent with the three therapies, although hyperglycemia was more common with prednisolone than with budesonide. The authors conclude that nebulized budesonide is as effective as oral prednisolone in the management of acute exacerbations of COPD.

    To determine the effect of stopping high-dose inhaled glucocorticoids in patients with COPD, van der Valk and coworkers (36) did a double-blind randomized study in 244 patients who had received inhaled fluticasone propionate (1,000 µg daily) for 4 months. Over the subsequent 6 months, 57% of the 121 patients in the placebo group developed at least one exacerbation as compared with 47% of the 123 patients in the fluticasone group. The hazard ratio of a first exacerbation was 1.5 in the placebo versus the fluticasone group. Measures of quality of life, in terms of total score, activity domain, and symptom domain were higher in the fluticasone group than in the placebo group. The authors conclude that the discontinuation of inhaled glucocorticoids in patients with COPD leads to an increased risk of exacerbation and a deterioration in the quality of life.

    The effect of inhaled glucocorticoids on the profile of inflammatory cells in the airways of patients with COPD is not known. Accordingly, Hattotuwa and coworkers (37) did a double-blind randomized trial of inhaled fluticasone propionate (500 µg twice daily) versus placebo in 31 patients with COPD. Bronchial biopsies at three months revealed no difference between the groups in the primary endpoints: number of CD8+ cells, CD68+ cells, and neutrophils (which are considered important in COPD). Patients receiving fluticasone showed a reduction in the ratio of CD8 to CD4 cells in the epithelium and a reduction in the number of mast cells in the subepithelium. Patients receiving fluticasone had an improvement in symptoms and fewer exacerbations. The authors conclude that inhaled fluticasone propionate has no effect on the major inflammatory cell types in the airways of patients with COPD, although it reduces the ratio of CD8 to CD4 cells in the epithelium and the number of mast cells in the subepithelium. An editorial commentary by Pauwels (38) accompanies this article.

    In 691 patients with COPD, Mahler and coworkers (39) did a randomized controlled comparison of inhaled salmeterol (50 µg), fluticasone propionate (500 µg), the combination of salmeterol and fluticasone, and placebo. Agents were inhaled via a Diskus device twice daily for 24 weeks. At the endpoint, the increase in predose FEV₁ was greater with the fluticasone-salmeterol combination (156 ml) than with salmeterol (107 ml) and placebo (-4 ml). The increase in 2-hour postdose FEV₁ was greater with the fluticasone¨Csalmeterol combination (261 ml) than with fluticasone (138 ml) and placebo (28 ml). Improvements in dyspnea were also greater with the combination therapy. The authors conclude that combination of fluticasone propionate and salmeterol delivered via a Diskus device achieves greater improvement in lung function and dyspnea than either agent on its own.

    To determine the relationship between use of glucocorticoids, bone mineral density, and fracture, Walsh and coworkers (40) studied patients who had taken continuous or frequent courses of oral glucocorticoids for asthma, COPD or idiopathic pulmonary fibrosis over the preceding six months. Of 117 patients, 48% were women, 58% had osteoporosis, and 61% had a vertebral fracture. The presence of a vertebral fracture was related to bone mineral density of the femoral neck (measured by X-ray absorptiometry): odds ratio was 1.6 for a reduction of 1 SD in density. Between the highest and lowest quartile dose of prednisolone, the risk of vertebral fracture increased 4.4-fold; adding bone density of the femoral neck did not alter the relationship. The authors conclude the risk of vertebral fracture is strongly related to the cumulative dose of prednisolone and that this effect is independent of its more modest effect on bone mineral density.

    To determine whether the use of inhaled glucocorticoids are associated with the development of a hip fracture, Hubbard and coworkers (41) did a case¨Ccontrol study of 16,341 cases of hip fracture in a general practice research database and 29,889 control subjects. After adjusting for potential confounders, conditional logistic regression revealed an association between hip fracture and inhaled glucocorticoids (odds ratio, 1.26). After adjusting for annual courses of oral glucocorticoids, the odds ratio was reduced to 1.19. Hip fractures displayed a dose¨Cresponse relationship to inhaled glucocorticoids. The authors conclude that use of inhaled glucocorticoids is associated with the development of hip fracture in older subjects.

    Experimental protease inhibitors.

    In a rat model of emphysema, the retinoid, all-trans-retinoic acid, reverses anatomic and physiologic signs of emphysema. Mao and coworkers (42) tested the feasibility of this agent in 20 patients with severe emphysema using a double-blind crossover design over 6 months. The treatment was generally well tolerated. Side effects included skin changes, transient headaches, hyperlipidemia, and musculoskeletal pains. Pulmonary function and computed tomographic images did not change. Plasma drug levels varied appreciably among subjects and decreased over time in 35% of the participants. The authors conclude that it is feasible to undertake a trial of therapy with all-trans-retinoic acid in patients with emphysema.

    ONO-6818 is a novel oral agent that inhibits neutrophil elastase. To investigate its effect, Kuraki and coworkers (43) studied four groups of rats. Oral administration of ONO-6818 1 hour before application of human neutrophil elastase ameliorated the increases in lung myeloperoxidase activity, hemoglobin, and neutrophil counts in bronchoalveolar fluid at 6 hours. Eight weeks later, the rats treated with ONO-6818 had less severe increases in functional residual capacity, total lung capacity, lung compliance, and mean linear intercept. The authors conclude that the induction of emphysema by human neutrophil elastase is inhibited by the oral neutrophil elastase inhibitor, ONO-6818, mainly through minimizing lung hemorrhage and the accumulation of neutrophils in the lung.

    To determine whether an orally active inhibitor of serine elastase, ZD 0892, decreases emphysematous lung destruction, Wright and coworkers (44) exposed guinea pigs to cigarette smoke. Acute exposure to smoke caused increased lavage neutrophils and increased desmosine and hydroxyproline (measures of elastin and collagen breakdown). These changes were reduced by the elastase inhibitor. Exposure to cigarette smoke every day for six months produced emphysema and caused increases in lavage neutrophils, desmosine, and hydroxyproline, and in plasma tumor necrosis factor-. The elastase inhibitor returned the lavage levels of neutrophils, desmosine and hydroxyproline to control values, decreased tumor necrosis factor- by 30%, and decreased the airspace enlargement by 45%. Exposure of animals to smoke plus the elastase inhibitor for two months, preceded by exposure to smoke for four months, did not protect against the development of emphysema. Mice exposed to smoke showed increases in gene expression of neutrophil chemoattractant macrophage inflammatory protein-, macrophage chemoattractant protein-1, and tumor necrosis factor-; these changes were prevented or decreased by the elastase inhibitor. The authors conclude that a serine elastase inhibitor ameliorates the inflammatory and destructive effects of cigarette smoke and that these effects are mediated in part by neutrophils and the production of tumor necrosis factor-.

    Other Therapies

    Lung volume reduction surgery.

    The mismatch between the size of the lungs and the size of the chest cavity in patients with emphysema is thought to be an important determinant of the reduced forced vital capacity (FVC) and FEV₁ in this condition. In 13 patients undergoing lung volume reduction surgery, Fessler and coworkers (45) found that the ratio of residual volume to total lung capacity¡ªa measure of the mismatch between lung size and chest size¡ªwas the only independent predictor of the increase in FVC after surgery. Of the increase in FEV₁ after surgery, 70% was attributable to the increase in FVC and the remainder to the increase in FEV₁/FVC ratio. In another group of 78 patients undergoing lung volume reduction surgery, the ratio of residual volume to total lung capacity was again correlated with the increase in FVC after surgery; the ratio, however, did not predict the increase in FEV₁. The authors conclude that the ratio of residual volume to total lung capacity is the major determinant of the increase in forced vital capacity achieved by lung volume reduction surgery.

    In 12 patients with severe emphysema (FEV_1, 0.69 liters; 23% predicted) undergoing lung volume reduction surgery, Mineo and coworkers (46) assessed right ventricular function before and 6 months after the surgery. Surgery produced a 59% increase in FEV₁, a 23% decrease in the ratio of residual volume to total lung capacity, a 12% increase in cardiac index during rest, and a 9% increase in right-ventricular stroke volume. During submaximal exercise, cardiac index increased by 22%, right-ventricular stroke volume increased by 28%, and right-ventricular ejection fraction increased by 20% after surgery. The improvement in ejection fraction during exercise was correlated with the decrease in the ratio of residual volume to total lung capacity after surgery (r = -0.68). The authors conclude that lung volume reduction surgery produces an improvement in right ventricular performance in patients with emphysema, especially during exercise.

    ₁-Antitrypsin replacement therapy.

    In 12 patients with -antitrypsin deficiency, Stockley and coworkers (47) studied the effect of four infusions of Prolastin at weekly intervals on airway inflammation. The serum level of -antitrypsin rose and was maintained above the protective threshold. One week after the first infusion, the level of -antitrypsin in expectorated sputum increased from 0.17 to 0.43 µm (equivalent to the value in normal subjects). Chemoattractant B₄ and elastase activity in the sputum samples decreased. The authors conclude that short-term therapy with Prolastin restores airway concentrations of ₁-antitrypsin to normal and it decreases the level leukotriene B₄ (a major mediator of neutrophil recruitment and augmentation) in airway secretions.

    Outcome

    To determine whether COPD interferes with a person¡¯s ability to work, Sin and coworkers (48) analyzed data from 12,436 participants in NHANES III (Third National Health and Nutrition Examination Survey) study, 8.6% of whom reported COPD. Compared with participants without COPD, those reporting COPD were 3.9% less likely to be in the labor force. The decreased likelihood of being in the labor force was proportional to disease severity: 3.4%, 3.9%, and 14.4% for subjects with mild, moderate and severe COPD, respectively. The decrease in ability to work was estimated to cause a loss of $9.9 billion in the United States. The authors conclude that a self-report of COPD is associated with a considerable reduction in a person¡¯s ability to work.

    Workshops

    In a summary report from a NHLBI workshop, Croxton and colleagues (49) review future directions for research on COPD.

    AIR POLLUTION

    TOP

    CONTENTS

    CHRONIC OBSTRUCTIVE PULMONARY...

    AIR POLLUTION

    PULMONARY VASCULAR DISORDERS AND...

    LUNG TRANSPLANTATION

    PLEURAL DISORDERS

    LUNG CANCER

    REFERENCES

    Air Pollution¨CGeneral

    To determine whether concentrated ambient air particles induce pulmonary inflammation in normal rats and in rats with chronic bronchitis, Saldiva and coworkers (50) exposed four groups of rats (some healthy and some with chronic bronchitis secondary to sulfur dioxide) to filtered air or to concentrated ambient air particles for five hours a day for three consecutive days. Concentrated ambient air particles caused an increase in neutrophils in the bronchoalveolar fluid of both the normal rats and the rats with chronic bronchitis. The particles caused an increase in the numerical density of neutrophils in the alveolar walls only in normal rats; the density was greater in the central regions than in the peripheral regions of the lung. A dose-dependent relationship was found between many components of concentrated ambient air particles (especially vanadium and bromine) and neutrophils and lymphocytes in bronchoalveolar fluid. The authors conclude that short-term exposure to concentrated ambient air particles induces a significant inflammatory reaction in the lungs of rats.

    Particulate air pollution is associated with cardiovascular morbidity and mortality. To investigate this association, Nemmar and coworkers (51) studied the effect of intravenous and intratracheal administration of ultrafine (60 nm) polystyrene particles on thrombus formation in a hamster model. Intravenous administration of unmodified particles had no effect on thrombus formation. Intravenous administration of amine-polystyrene particles enhanced thrombosis at high but not at low concentrations. High concentrations of carboxylate-polystyrene particles inhibited thrombus formation. Intratracheal instillation of amino-polystyrene particles caused an increase in thrombus formation, whereas unmodified particles and carboxylate-polysterene particles had no effect. Unmodified particles did not alter the aggregation of platelets in human plasma induced by ADP, whereas carboxylate-polystyrene particles weakly enhanced platelet aggregation. Amine-polystyrene particles were sufficient to induce platelet aggregation on their own and strongly enhanced aggregation induced by ADP. The authors conclude that the presence of ultrafine particles in the circulation increases the tendency toward thrombosis, resulting in part from platelet activation and depending on the surface charge of the particles.

    To determine whether antioxidant vitamins could modulate the adverse effect of air pollution on lung function in children, Romieu and coworkers (52) did a double-blind randomized study in 158 children with asthma who lived in Mexico City. During the 31-month study, the average maximum level of ozone was 102 ppb and the mean 24-hour average level of particulates with a mass median diameter of less than 10 µm (PM₁₀) was 57 µg per m³. Pulmonary function was measured twice weekly. In the placebo group, the children with moderate and severe asthma showed an inverse relationship between the level of ozone (on the day before spirometry) and peak expiratory flow (-15 ml per second per 10 ppb), forced expiratory flow (FEF_25¨C75, -13.3 ml per second per 10 ppb), and FEV₁ (-4.6 ml per 10 ppb). In children treated with vitamin E (50 mg daily) and vitamin C (250 mg daily), no association was seen between ozone and lung function. The authors conclude that antioxidant supplements might modulate the impact of exposure to ozone on the small airways of children with moderate to severe asthma.

    To determine whether exposure to ambient air pollutants affects the growth of lung function in children, Gauderman and coworkers (53) studied 2,081 fourth-grade children (average age, 9.9 years). Exposure to acid vapor, nitrogen dioxide, particles with an aerodynamic diameter of less than 2.5 µm (PM_2.5), and elemental carbon were associated with significant deficits in the growth of lung function. Across the range of acid exposure, for example, the average annual growth rates of MMEF and FEV₁ were reduced by 11% and 5%, respectively. Exposure to acid vapor was associated with a decrease in the ratio of MMEF to FVC, whereas exposure to ozone was associated with a reduced rate of growth in PEF. Children spending more time outdoors experienced greater deficits in lung function. The authors conclude that exposure to ambient levels of air pollutants has a detrimental effect on growth of lung function in children.

    To determine the relationship between exposure to air pollution related to traffic and the development of asthmatic symptoms, allergic diseases, and respiratory infections, Brauer and coworkers (54) studied a birth cohort of 4,146 children. Outdoor concentrations of traffic-related air pollutants were modeled for the home of each subject. Adjusted odds ratios for wheezing, physician-diagnosed asthma, infections of the ear, nose or throat, and serious colds at 2 years of age were associated with air pollutants; some of the associations reached borderline statistical significance. The authors conclude that traffic-related air pollution may be associated with the prevalence of respiratory illness at 2 years of age.

    Diesel Exhaust

    Takano and coworkers (55) determined whether diesel exhaust particles enhance lung inflammation caused by endotoxin in mice. Instillation of diesel exhaust particles into the trachea of mice synergistically enhanced the lung inflammation caused by endotoxin, which was characterized by neutrophil sequestration, interstitial edema, and alveolar hemorrhage. Given alone, diesel exhaust particles increased the lung expression of Toll-lik

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