© 2004 American Thoracic Society doi: 10.1164/rccm.2312007
Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2003Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois Correspondence and requests for reprints should be addressed to Martin J. Tobin. M.D., Division of Pulmonary and Critical Care Medicine, Hines Veterans Affairs Hospital, Route 111N, Hines, IL 60141. E-mail: mtobin2{at}lumc.edu
Chronic Obstructive Pulmonary Disease (49) Epidemiology (3) Alpha1-Antitrypsin Deficiency (4) Cellular, Molecular, and Anatomical Abnormalities (12) Lung Inflammation (2) Exhaled Markers (3) Pathophysiologic and Radiologic Studies (1) Pulmonary Vasculature (1) Control of Breathing and Exercise (3) Respiratory Muscles (3) Peripheral Muscles (5) Drug Therapy (7) Theophylline (1) Glucocorticoids (4) New Drugs (2) Other Therapies (5) Lung Volume Reduction (1) Rehabilitation and Oxygen Therapy (3) Workshops and Review (1) Air Pollution (4) General Air Pollution (2) Diesel Exhaust (2) Pulmonary Vascular Disorders and Related Disorders (14) Pulmonary Hypertension (7) Secondary Pulmonary Hypertension (1) Molecular and Pathophysiologic Mechanisms (3) Diagnosis (1) Treatment (2) Thromboembolic Disorders (3) High Altitude (1) Sickle Cell Disease (3) Lung Transplantation (10) Lung Preservation and Ischemia Reperfusion Injury (3) Obliterative Bronchiolitis (4) Rejection (2) In Lymphangiomyomatosis (1) Pleural Disorders (6) Physiology/Pathophysiology (2) Diagnostic Techniques (3) Pleurodesis (1) Lung Cancer and Oncologic disorders (12) Diagnosis (6) Studies of Molecular Mechanisms (1) Leukemia (1) Stem Cell Transplantation (4)
Epidemiology To determine whether obstructive airways disease is associated with sleep-disordered breathing, Sanders and coworkers (1) analyzed polysomnography and spirometry data from 5,954 participants in the Sleep Heart Health Study. Obstructive airway disease, defined as a ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) of less than 70%, was present in 1,132 participants; involvement was mostly mild (FEV1/FVC, 63.8%). A respiratory disturbance index of greater than 10 events per hour was equally prevalent in subjects with obstructive airway disease and in subjects without obstructive airway disease, 22.3 versus 28.9%. In subjects without sleep apnea–hypopnea, the adjusted odds ratio for sleep desaturation (more than 5% of sleep time with saturation below 90%) exceeded 1.9 when FEV1/FVC was less than 65%. The authors conclude that mild obstructive airways disease is not associated with sleep apnea–hypopnea although an FEV1/FVC of less than 65% is associated with sleep desaturation. An editorial commentary by Fleetham (2) accompanies this article. In a pulmonary perspective, Snider (3) discusses the nosology of chronic obstructive pulmonary disease (COPD).
Alpha1-Antitrypsin Deficiency
Although serine elastase inhibitors have been proposed in the treatment of emphysema, little is known of their efficacy. To investigate this question, Churg and coworkers (5) studied transgenic mice that produce extremely low levels of human
The American Thoracic Society and the European Respiratory Society (7) present a statement on standards for the diagnosis and management of
Cellular, Molecular, and Anatomical Abnormalities To assess the role of neutrophilia and neutrophil chemokine and receptor gene expression in severe exacerbations of COPD, Qiu and coworkers (9) did endobronchial biopsies in 15 patients with COPD who were intubated for an acute exacerbation (FEV1, 36% of predicted), 7 patients with stable COPD (FEV1, 51% of predicted), and 15 control subjects intubated for a nonrespiratory surgical procedure (FEV1, 98% of predicted). Compared with the patients with stable COPD, the patients with an acute exacerbation of COPD had a 97-fold increase in neutrophilia; gene expression for epithelial-derived neutrophil attractant–78 (CXCL5) was increased 6-fold, interleukin-8 (CXCL8) was increased 6-fold, CXCR1 was increased 3-fold, and CXCR2 was increased 7-fold. In patients with an exacerbation of COPD, the number of neutrophils was correlated with cells positive for CXCR2 messenger RNA (r = 0.79), but not with cells positive for CXCR1 messenger RNA. Neutrophil number was not correlated with the duration of intubation or viral infection. The authors conclude that a severe exacerbation of COPD causes increased neutrophil recruitment that is associated with upregulation of the neutrophil-selective cytokines, CXCL5 (epithelial-derived neutrophil attractant–78) and CXCL8 (interleukin-8), and CXCR1 and CXCR2, the relevant receptors on which these neutrophil chemoattractant ligands act. An editorial commentary by Saetta and coworkers (10) accompanies this article.
Recent data reveal that both neutrophils and macrophage-derived metalloelastase (MMP-12) are required for the breakdown of connective tissue induced by acute cigarette smoke. Churg and coworkers (11) investigated the link between these mechanisms. Acute cigarette smoke exposure caused rapid increases in whole-lung activation of nuclear factor-
Little is known about the pathogenesis of the small airway disease (a form of airway remodeling) in cigarette smokers. To better understand the mechanism, Wang and coworkers (13) exposed rat tracheal explants to cigarette smoke and then maintained them in an air–organ culture. At 24 hours after smoke exposure, gene expression of procollagen was increased in a dose-dependent manner and hydroxyproline, a measure of collagen content, was increased. Greater increases in gene expression of procollagen occurred with repeated smoke exposure. The increase in procollagen gene expression was prevented by a selective inhibitor of nuclear factor- Extracellular matrix metalloproteinase inducer (EMMPRIN) is present in the lung during development but expression in the healthy adult lung is minimal. To determine whether EMMPRIN might be associated with smoking-induced injury, Betsuyaku and coworkers (14) did bronchoalveolar lavages in 7 never-smokers, 16 former smokers, and 58 current smokers (7 of the former smokers and 32 of the current smokers had emphysema on computed tomography). Levels of EMMPRIN were higher in current smokers (315 pg per ml) and former smokers (175 pg per ml) than in never smokers (31 pg per ml); the levels did not discriminate between the presence or absence of emphysema among the smokers. Immunochemistry of smokers' lung tissue revealed EMMPRIN in bronchiolar epithelium and alveolar macrophages; messenger RNA for EMMPRIN in alveolar macrophages did not differ between current and never-smokers. Matrix metalloproteinase-1 was detected in bronchoalveolar fluid of some smokers, but not in the never-smokers. The authors conclude that smoking is associated with increases in extracellular matrix metalloproteinase inducer (EMMPRIN) in bronchoalveolar fluid and that the increase persists for a long time after smoking cessation. Because glucocorticoids can affect matrix metalloproteinases, Choe and coworkers (15) studied the effect of methylprednisolone on lung structure in adult rats. Daily methylprednisolone (2 mg per kg) for 1, 2, or 4 weeks produced an increase in mean linear intercept and a decrease in the surface–volume ratio. Animals also exhibited increased activity of matrix metalloproteinase-9. Rats treated with a broad-spectrum matrix metalloproteinase inhibitor (GM6001) did not develop emphysema. The authors conclude that methylprednisolone increases the activity of matrix metalloproteinases in rat lung and causes emphysema. In a state of the art review article, Ryu and colleagues (16) discuss bronchiolar disorders. In a report from an international workshop, Jeffery and colleagues (17) describe the methods used for the assessment of endobronchial biopsies in clinical research, and the application of these methods in studies of pathogenesis and treatment. In a state of the art review article, Kinnula and Crapo (18) discuss superoxide dismutase in lung disease. In a pulmonary perspective, Turino and Cantor (19) discuss the role of hyaluronan in respiratory injury and repair.
Lung Inflammation
In a mouse model of elastase-induced emphysema, Inoue and coworkers (21) investigated the mechanism for increased susceptibility to bacterial infection. Intratracheal infection with Streptococcus pneumoniae (103–107 cfu per mouse) increased mortality in a dose-dependent manner in emphysematous mice, but did not kill control mice. Compared with control mice, the emphysematous mice had lower levels of total cells, neutrophils, tumor necrosis factor-
Exhaled Markers The use of exhaled breath condensates for assessing lung inflammation is complicated by dilution from varying amounts of water vapor. In 18 healthy subjects, Effros (24) determined whether conductivity of lyophilized samples can be used for estimating airway electrolyte concentrations and dilution of exhaled condensates by water vapor. The dilution was estimated by comparing concentrations of nonvolatile, reference indicators (total nonvolatile cations, urea, or conductivity), and assuming that concentrations in respiratory fluid and plasma are equivalent. The volatile cation, ammonium (NH4+), represented 93% of cations in the condensate. More than 99% of ammonium was removed by lyophilization, making it possible to use conductivity to estimate total nonvolatile ionic concentrations and facilitating analysis of urea. Estimates of dilution were equivalent for total cations (20,472), conductivity (21,019), and urea (18,818). The authors conclude that measurement of conductivity in lyophilized samples of exhaled breath condensates makes it possible to estimate the dilution of condensates by water vapor.
Pathophysiologic and Radiologic Studies
Pulmonary Vasculature
Control of Breathing and Exercise To examine factors influencing the reproducibility of the 6-minute walk test, Sciurba and coworkers (28) analyzed data on the first 761 patients entered into the National Emphysema Treatment Trial. Of these, 470 patients repeated the walk on the next day. Patients walked 7% more (66 ft) on the second day; intraclass correlation coefficient was 0.88 between days. Patients walking on a circular or oval course walked 92 ft more than did patients walking on a straight course. Course length had no effect on walking distance. The authors conclude that the training effect during a 6-minute walk test is less than previously reported, and that layout of the track influences the distance walked The American Thoracic Society and the American College of Chest Physicians (29) present a statement on cardiopulmonary exercise testing.
Respiratory Muscles To determine the relationship between diaphragmatic fiber type and severity of airway obstruction, Levine and coworkers (31) did biopsies of the costal diaphragm in 40 patients with COPD (FEV1 ranged from 16 to 118% of predicted). The relationship between the proportion of pure Type I fibers and FEV1 was exponential (r = 0.844): the proportion showed little increase as FEV1 decreased from 118 to 60% of predicted, but thereafter increased appreciably. Patients with severe COPD exhibited lower levels of maximal specific force in single fibers than did patients with normal lung function. Type I fibers generated lower force than did Type II fibers. The authors conclude that patients with COPD develop an increase of Type I fibers in their costal diaphragm when FEV1 falls below 60% of predicted and that force generation is also decreased secondary to adaptations within each fiber type. In a state of the art review article on disorders of the respiratory muscles, Laghi and Tobin (32) discuss the effect of COPD on the respiratory muscles.
Peripheral Muscles Oxidative stress arising in exercising muscle may contribute to the peripheral muscle dysfunction of COPD. To determine whether quadriceps exercise induces oxidative stress and whether the stress decreases muscle endurance, Couillard and coworkers (35) studied 12 patients with COPD (FEV1, 33% predicted) and 10 healthy subjects. Biopsies of the vastus lateralis were obtained before and 48 hours after exercise. Quadriceps endurance was less in the patients than in the control subjects: 378 versus 843 seconds. At 48 hours, patients, but not the control subjects, displayed increases in muscle lipid peroxidation and oxidized protein; the control subjects, but not the patients, displayed an increase in peroxidase glutathion activity. Endurance time was inversely correlated with both muscle lipid peroxidation (r = –0.66) and oxidized protein (r = –0.70). The authors conclude that quadriceps exercise increased oxidative stress but not antioxidant activity in patients with COPD, and that the increase in oxidative stress was correlated with a decrease in quadriceps endurance. To determine whether severity of COPD influences the degree of quadriceps fatigability after single muscle contractions, Mador and coworkers (36) studied 8 patients with severe COPD (FEV1, 26% predicted), 11 patients with mild-to-moderate COPD (FEV1, 50% predicted), and 10 healthy subjects. Maximum voluntary contraction of the right quadriceps achieved a force of 44 kg in patients with severe COPD, 49 kg in patients with mild-to-moderate COPD, and 58 kg in healthy subjects. Three sets of 10 maximum voluntary contractions of the quadriceps achieved greater fatigability (measured as the decrease in potentiated twitch force during magnetic stimulation of the femoral nerve) of the quadriceps in patients with severe COPD than in patients with mild-to-moderate COPD or the healthy subjects. The fall in twitch force in patients with mild-to-moderate COPD was not significantly different from healthy subjects. The authors conclude that patients with severe COPD display greater fatigability of the quadriceps muscle than do healthy subjects or patients with mild-to-moderate COPD. When cycling, patients with COPD often stop because of leg effort rather than dyspnea. To determine whether the response might differ when patients walk versus when they cycle, Man and coworkers (37) studied 84 patients with COPD (FEV1, 41% of predicted). Dyspnea alone was a more common limiting symptom during incremental walking than during incremental cycling (81 versus 34%) and during endurance walking than during endurance cycling (75 versus 29%). Twitch stimulation of the quadriceps was performed in 12 of the patients. Walking did not decrease twitch tension of the quadriceps, whereas cycling caused a 17.1% decrease in twitch tension. The authors conclude that leg effort and fatigue of the quadriceps are infrequent after walking in patients with COPD.
Drug Therapy
Glucocorticoids. Although observational studies in patients with COPD have revealed improved survival with use of inhaled glucocorticoids, the benefit has not been seen with randomized trials. One explanation for the discrepancy is the misclassification of users and nonusers because of immortal person–time bias; this bias arises because some patients will have died at the point of assessing glucocorticoid exposure, and thus patients who survive will have a longer opportunity for being exposed to glucocorticoids. To avoid the problem of immortal person–time bias, Fan and coworkers (41) analyzed pharmacy refill records in 2,686 patients with COPD in a time-dependent manner. Mortality was not significantly decreased for average inhaled glucocorticoid use at either low dose (hazard ratio, 0.96) or medium/high dose (hazard ratio, 0.86). Likewise, mortality was not significantly decreased with recent inhaled glucocorticoid use at low dose (hazard ratio, 0.80) or medium/high dose (hazard ratio, 0.88). Use of inhaled glucocorticoids was not associated with hospitalizations or exacerbations secondary to COPD. The authors conclude that use of inhaled glucocorticoids, either in terms of dosage or length of use, is not associated with either exacerbations of COPD or mortality from COPD. To determine the effect of glucocorticoids on cytokine release by alveolar macrophages, Culpitt and coworkers (42) did bronchoalveolar lavage in 15 patients with COPD (FEV1/FVC, 53%) and 15 cigarette smokers without airway obstruction. Basal release of interleukin-8 by macrophages was more than five times greater in the patients than in the smokers; release of granulocyte macrophage-colony stimulating factor was equivalent in the two groups. Both interleukin-1ß and cigarette smoke media increased the release of both interleukin-8 and granulocyte macrophage-colony stimulating factor from both the patients and the smokers. Dexamethasone did not inhibit the basal level or the stimulated release of interleukin-8 from the macrophages of the patients, although it inhibited release in the smokers. Dexamethasone inhibited both the basal release of granulocyte macrophage-colony stimulating factor and the release induced by interleukin-1ß, but it did not inhibit the release induced by cigarette smoke media. The authors conclude that the lack of efficacy of glucocorticoids in COPD might be secondary to relative insensitivity of macrophages in the respiratory tract to glucocorticoids.
New drugs.
Other Therapies
Rehabilitation and oxygen therapy. Maintaining long-term improvement after pulmonary rehabilitation has been difficult. In 172 patients with chronic lung disease, Ries and coworkers (48) tested the value of a telephone–maintenance program after rehabilitation in a randomized trial. Patients were randomized to 12 months of maintenance intervention (weekly phone calls plus monthly supervised reinforcement session) or standard care, and followed for 24 months. During the 12 months of intervention, the maintenance intervention group achieved better exercise tolerance (maximum treadmill workload and 6-minute walk distance), better overall health status ratings, and a decrease in hospital days. The groups did not differ in measures of pulmonary function, dyspnea, self-efficacy, quality of life, or general health use. By 24 months, group differences were no longer present and patients returned to levels close to, but above, prerehabilitation measures. The authors conclude that a maintenance program of weekly telephone calls and monthly supervised sessions only modestly enhance the maintenance of benefits after pulmonary rehabilitation.
Workshops and review articles.
General Air Pollution To determine whether the presence of a contributing respiratory disease increases the effect air pollution on mortality from nonrespiratory disease, De Leon (50) modeled the short-term association between ambient particulate matter (10 µm or less in aerodynamic diameter) and mortality in New York City between 1985 and 1994. Compared with subjects without a contributing respiratory disease, the subjects who had a contributing respiratory disease had higher mortality for circulatory deaths (relative risk, 1.066) and cancer deaths (relative risk, 1.129). The relationships were observed only in subjects who were 75 years of age or older. The authors conclude that older individuals are at increased risk of mortality from air pollution when coexisting respiratory disorders are also present. The American Thoracic Society (51) presents a document on lung diseases and the environment.
Diesel Exhaust
Senechal and coworkers (53) investigated whether diesel exhausts favor type 2 helper T cell (Th2)–associated allergic reactions either by increasing production of Th2-associated chemokines and their associated receptors or by decreasing type 1 helper T cell (Th1)–attracting chemokines and chemokine receptors. Exposure of peripheral blood mononuclear cells from patients with asthma to diesel induced release of I-309; this effect did not occur with allergen exposure. Both diesel and Der p 1 induced early but transient release of monokine induced by interferon-
Pulmonary Hypertension Secondary pulmonary hypertension. Nunes and coworkers (54) reported a series of 82 patients with human immunodeficiency virus (HIV)–associated pulmonary arterial hypertension. Pulmonary hypertension was the direct cause of death in 72% of the patients. Survival rate in the overall population was 73% at 1 year, 60% at 2 years, and 47% at 3 years. Compared with New York Heart Association functional Class I-II, patients in functional Class III-IV at the time of diagnosis had lower survival rates at 1 year (60 versus 100%), 2 years (45 versus 90%), and 3 years (28 versus 84%). In patients with functional class III-IV, univariate analysis revealed that prognosis was related to CD4 lymphocyte count of more than 212 cells mm–3, use of combination antiretroviral therapy, and use of epoprostenol. Multivariate analysis revealed CD4 lymphocyte count as the only independent predictor of survival, probably because combination antiretroviral therapy and epoprostenol therapy were linked in these patients. The authors conclude that pulmonary artery hypertension has an independent negative effect on prognosis in patients with HIV infection, and that epoprostenol should be considered in the treatment of patients with severe pulmonary hypertension.
Molecular and pathophysiologic mechanisms. The mitogenic effect of serotonin on smooth muscle cells of the pulmonary vasculature is mediated by the serotonin transporter, 5-hydroxytryptamine transporter (5-HTT); the constricting effect of serotonin is mediated by the receptors, 5-HT1B/1D and 5-HT2A. Marcos and coworkers (56) investigated the role of the serotonin transporter and receptors on the development of pulmonary hypertension in mice exposed to chronic hypoxia (10% oxygen for 2 weeks). Development of right-ventricular hypertrophy was decreased by 12% with citalopram and by 14% with fluoxetine, two inhibitors of the serotonin transporter (5-HTT); pulmonary vessel muscularization was also decreased with both treatments. Two receptor antagonists, GR127935 (selective antagonist of 5-HT1B/1D) and ketaneserin (selective antagonist of 5-HT2A) had no effect on right-ventricular hypertrophy or pulmonary vessel muscularization. The authors conclude that the serotonin transporter, 5-HTT, plays a key role in modulating the pulmonary vascular remodeling caused by hypoxia. The endothelial responses to circumferential vascular stretch are poorly defined. In two different models of vascular stretch in the intact lung, Kuebler and coworkers (57) studied the effect of circumferential stretch on lung endothelial production of nitric oxide. In isolated–perfused rat lungs, increases in vascular pressure caused stretch-dependent increases in nitric oxide, which were localized to capillary endothelial cells; the response was inhibited by blockers of nitric oxide synthase. In isolated–perfused mouse lungs, vascular stretch (induced by negative-pressure ventilation) induced phosphorylation of Akt and endothelial nitric oxide synthase in lung endothelial cells; production of nitric oxide was also increased. In both models, the endothelial responses to stretch were abrogated by phosphatidylinositol-3-OH kinase inhibitors. The authors conclude that circumferential vascular stretch activates the production of nitric oxide in the pulmonary endothelial cells by a signaling cascade that involves phosphatidylinositol-3-OH kinase, Akt, and endothelial nitric oxide synthase, and that this response is independent of mechanical factors causing vascular distension.
Diagnosis.
Treatment. Oral sildenafil is a more potent acute pulmonary vasodilator than is inhaled nitric oxide in patients with pulmonary hypertension. In 12 patients with inoperable chronic thromboembolic pulmonary hypertension that was progressive despite long-term anticoagulation, Ghofrani and coworkers (60) assessed the effect of oral sildenafil. After 6 months of treatment, sildenafil resulted in a decrease in pulmonary vascular resistance index (1,935 to 1,361 dyn · s · cm–5), an increase in cardiac index (2.0 to 2.4 liters per minute per m2), and an increase in 6-minute walking distance (312 to 366 m). The authors conclude that oral sildenafil achieves beneficial effects in patients with chronic thromboembolic pulmonary hypertension.
Thromboembolic Disorders Because magnetic resonance angiography does not yield optimal images in patients who cannot breath-hold, a motion-compensated projection might be an improvement. In nine pigs with artificially induced pulmonary emboli, Haage and coworkers (62) compared three imaging techniques against conventional angiography. Conventional angiography revealed 43 filling defects at lobar and segmental levels. Two independent readers achieved the following sensitivities: 72% and 70% for spiral computed tomography; 79% and 81% for magnetic resonance angiography; and 98% and 98% for real-time magnetic resonance sequence without a breath-hold. The authors conclude that real-time magnetic resonance imaging that does not require a breath-hold is comparable to conventional angiography in the detection of pulmonary angiography. Use of femoral-vein catheters is associated with a high risk of thrombosis despite prophylactic therapy. To assess the cost-effectiveness of routine lower extremity Doppler ultrasound screening in patients with femoral vein catheters, Cox and coworkers (63) developed a decision model. The analysis was based on a hypothetical cohort of 60-year-old medical patients being treated for acute respiratory failure. The costs of the ultrasound strategy were $8,688 per quality-adjusted life-year gained, $5,305 per pulmonary embolism averted, and $99,286 per death from pulmonary embolism averted. By varying in-hospital mortality, prevalence of deep-vein thrombosis, and ultrasound accuracy, the best-case cost was $1,170 and the worst-case cost was $35,342 per quality-adjusted life-year gained. Allowing for variation in variables of uncertain value, the median cost was $12,793 per quality-adjusted life-year gained. The authors conclude that routine ultrasound screening of patients with femoral vein catheters may improve outcomes at acceptable costs.
High Altitude
Sickle Cell Disease More that 40% of patients who develop acute chest syndrome secondary to sickle-cell disease have fat droplets in their alveolar macrophages, which are suggestive of pulmonary fat embolism. To determine the reliability of induced sputum for diagnosing fat embolism, Lechapt and coworkers (67) did two studies. In 20 patients with acute chest syndrome, the number of Oil Red O–stained macrophages in induced sputum was correlated with the number in bronchoalveolar lavage fluid (Spearman's coefficient, 0.66). In a second group of 60 patients with episodes of acute chest syndrome, sputum induction was successful in 47 patients. A diagnosis of pulmonary fat embolism (based on 5% of macrophages staining with Oil Red O) was made in 29 of the 47 patients with acute chest syndrome (61.7%) and none of 9 patients who did not have acute chest syndrome. Compared with patients who had acute chest syndrome but did not have pulmonary fat embolism, the patients with fat embolism were more likely to have additional extrathoracic pain (76 versus 50%), neurological symptoms (7 versus 0%), abnormal transaminases (28 versus 17%), and a lower differential platelet count (–49 versus 85). The authors conclude that staining of induced sputum is a useful test for diagnosing pulmonary fat embolism in patients who have acute chest syndrome secondary to sickle-cell disease.
Lung Preservation and Ischemia Reperfusion Injury Sugita and coworkers (68) created a canine single-lung transplant model to determine the impact of transplantation-associated injury on the clearance mechanisms of pulmonary edema. After 3 hours of preservation and 4 hours of reperfusion, alveolar liquid clearance in ex vivo liquid-filled lung preparations was lower in transplanted (left) lungs than in native (right) lungs. The transplanted lung did not respond to the ß-agonist, terbutaline. In vivo studies confirmed the ex vivo results. Molecular analyses revealed a decrease in messenger RNA and protein expression for the epithelial sodium channel, but not sodium, potassium-ATPase, in the transplanted lung. The authors conclude that the injury resulting from lung preservation and transplantation causes a decrease in the ability to clear lung edema. Inhalation of nitric oxide has been advocated as a method to prevent ischemia–reperfusion injury after lung transplantation. Meade and coworkers (69) did a randomized controlled trial of inhaled nitric oxide (22 ppm) versus placebo in 83 patients, initiated 10 minutes after reperfusion. PO2/FIO2 was equivalent in the nitric oxide and placebo groups (361 versus 351) on admission to the ICU. Severe hypoxemia (PO2/FIO2 less than 150) taken as an index of severe reperfusion injury, was present in 14.6% of the nitric oxide group and 9.5% of the control group. The nitric oxide and placebo groups had equivalent times to first trial of spontaneous breathing (medians of 25 versus 27 hours), successful extubation (32 versus 34 hours), ICU discharge (3 days for both), and hospital discharge (27 versus 29 days). Five patients in the nitric oxide and six in the placebo group died in the hospital. The authors conclude that inhaled nitric oxide shortly after reperfusion does not alter clinical outcome in patients undergoing lung transplantation. An editorial commentary by Glanville (70) accompanies this article.
Obliterative Bronchiolitis Noninvasive markers that predict the likelihood of acute rejection and bronchiolitis obliterans syndrome after lung transplantation have not been developed. Gimino and coworkers (73) did gene expression microarrays of bronchoalveolar cells obtained in 7 patients with acute rejection and 27 patients without rejection. Cell and differential counts were similar in the two groups. The acute rejection group exhibited upregulation of 135 genes, including genes involved in acute rejection, immune response genes with an unknown role in rejection, genes not known to have a role in rejection, and genes of unknown function. The acute rejection samples showed significant changes in gene expression for seven biological pathways. The authors conclude that microarray analysis of bronchoalveolar cells is a powerful tool for identifying genes and gene expression patterns indicative of acute rejection after lung transplantation.
To define the contributions of indirect and direct allorecognition pathways in chronic lung rejection, Chalermskulrat and coworkers (74) used the heterotopic tracheal transplantation model. Transplantation of wild-type tracheal allografts into MHC II–/– or H2-DM
Rejection Macrolide antibiotics have achieved beneficial actions in the treatment of panbronchiolitis in patients with cystic fibrosis. To determine whether patients with bronchiolitis obliterans syndrome would also benefit, Gerhardt and coworkers (76) administered azithromycin (250 mg three times a week for 14 weeks) to six patients with deteriorating allograft function. The six patients demonstrated a mean increase in FEV1 of 0.5 liter (range, –0.18 to 1.36 liter), representing an average improvement in FEV1 of 46%. The authors conclude that azithromycin may prove beneficial in patients with bronchiolitis obliterans following lung transplantation.
In Lymphangiomyomatosis
Physiology/Pathophysiology Intercellular adhesion molecule-1 is an adhesion molecule that plays a key role in cell-cell interactions involved in the recruitment of cells and immune responses. To determine the cellular source, control and activity of soluble intercellular adhesion molecule-1, Melis and coworkers (78) did thoracenteses in 9 patients with congestive heart failure, 8 patients with tuberculosis, and 15 patients with cancer. In patients with tuberculous and malignant effusions, dimeric soluble intercellular adhesion molecule-1 was released locally in the pleural compartment. The soluble adhesion molecule was shed from pre-expressed surface intercellular adhesion molecule-1 rather than produced de novo. CD45-positive leukocytes and cytokeratin-positive epithelial and mesothelial cells expressed intercellular adhesion molecule-1, suggesting that it originates from multiple cellular sources. Pleural macrophages caused the release of soluble intercellular adhesion molecule-1 via a mechanism depending on tumor necrosis factor-  . Soluble intercellular adhesion molecule-1 interfered with conjugate formation between LAK cells and K562 cells, suggesting that the adhesion molecule plays an immunosuppressive role. The authors conclude that soluble intercellular adhesion molecule-1 is shed from the surface of pleural cells in a regulated manner and is capable of modulating the immune response in the pleural space. To determine whether transforming growth factor-ß1 modulates fibrosis occurring in the pleural space, Sasse and coworkers (79) induced empyema in rabbits. Pleural fluid revealed increases in transforming growth factor-ß1 between the first two days and the eighth day after induction of empyema (8,100 versus 39,600 pg per ml). The level of transforming growth factor-ß1 in pleural fluid was proportional to pleural thickening (r = 0.70) and the number of fibroblasts in the visceral pleura (r = 0.68). The first increase of transforming growth factor-ß1 in pleura fluid (third day) occurred before the increase in fibroblasts (fourth day) and pleural thickness (fourth day). The authors conclude that transforming growth factor-ß1 increases in pleural fluid as fibrosis develops in experimental empyema and the increase is proportional to the extent of pleural space fibrosis.
Diagnostic Techniques In a pulmonary perspective, Heffner and colleagues (82) present a meta-analysis on use of likelihood ratios for diagnosing pleural effusions.
Pleurodesis
Diagnosis Up to half of patients with histologically normal lymph nodes have micrometastases detected by molecular techniques. To determine whether the expression of human telomerase reverse transcriptase (found by the reverse transcription-polymerase chain reaction) could detect micrometastatic disease, Wallace and coworkers (84) did fine-needle aspiration of lymph nodes (under endoscopic ultrasound) in 39 patients with non–small cell lung cancer and 12 control subjects (being evaluated for benign pancreatic or biliary disease). Human telomerase reverse-transcriptase was expressed in 10 of 16 pathologically positive lymph nodes, 18 of 57 pathologically negative lymph nodes from cancer patients, and 0 of 14 negative nodes from control subjects. Of 18 patients without pathologic evidence of mediastinal disease, 5 (28%) expressed telomerase in at least one lymph node (the clinical significance of this observation is not known). The authors conclude that ultrasound-guided fine-needle aspiration combined with molecular detection of telomerase expression can detect cancer-specific messenger RNA in lymph nodes. An editorial commentary by Massion and Carbone (85) accompanies this article. To determine whether the use of automated quantitative image cytometry of sputum cells as the first screening method results in superior detection of lung cancer, McWilliams and coworkers (86) studied 561 current or former smokers (with a smoking history at least 30 pack years). Sputum atypia, defined as at least 5 cells with abnormal DNA content, was found in 423 of the subjects (75.4%). Noncalcified pulmonary nodules were found in 259 of the subjects (46%). Of 14 primary lung cancers diagnosed (10 by computed tomography and 4 by autofluorescence bronchoscopy), 13 were found in subjects with sputum atypia. Automated quantitative image cytometry of sputum cells improved the cancer detection rate from 1.8 to 3.1%. A computed tomography scan on its own would have missed 29% of cancers. The authors conclude that 93% of lung cancers can be detected by finding atypical cells by automated quantitative image cytometry of sputum cells whereas 29% of lung cancers do not appear on computed tomography. An editorial commentary by Henschke (87) accompanies this article. Staging of patients with lung cancer is undertaken to minimize futile thoracotomies and yet not deny possible curative surgery. To assess the usefulness of endoscopic ultrasound with fine-needle aspiration under conscious sedation in providing tissue proof of inoperability in a single staging test, Fritscher-Ravens and coworkers (88) studied a consecutive cohort of 79 potentially operable patients with suspected or proven lung cancer. Thirty-nine patients were found inoperable. Sensitivities of three diagnostic procedures were: endoscopic ultrasound, 63%; computed tomography, 43%; and positron-emission tomography, 68%. Specificities were: endoscopic ultrasound, 100%; computed tomography, 91%, and positron emission tomography, 72%. The costs were: computed tomography alone, $549; computed tomography plus positron emission tomography, $2,799; and endoscopic ultra-fine needle aspiration plus computed tomography, $1,695. The authors conclude that the superior specificity and relatively low costs of endoscopic ultrasound combined with fine-needle aspiration make it a valuable method for identifying patients with inoperable lung cancer. An editorial commentary by Kern (89) accompanies this article.
Studies of Molecular Mechanisms
Leukemia
Stem Cell Transplantation It is possible that many of the tissues of the body may be actively replaced by circulating stem cells after hematopoietic stem cell transplantation. To determine whether tissues of the human lung might be derived from nonpulmonary sources, Suratt and coworkers (94) examined lung specimens from a cohort of 46 women who received stem cells from male donors. Tissue samples (obtained at diagnostic lung biopsy or autopsy) from three women were suitable for examination. Assessment for cytokeratin (epithelium) and platelet endothelial cell adhesion molecule (endothelium) was used in part to identify male cells. Some 36 to 42% of the endothelial cells and 3 to 8% of the epithelial cells were of donor origin. The authors conclude that chimerism (localization of donor-derived cells) occurs in the human lung after hematopoietic stem-cell transplantation. An editorial commentary by Robbins (95) accompanies this article.
Supported by a Merit Review grant from the Veterans Affairs Research Service Conflict of Interest Statement: M.J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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CHRONIC OBSTRUCTIVE PULMONARY...
B and gene expression of proinflammatory cytokines in both wild-type mice (MMP-12+/+) and mice lacking metalloelastase (MMP-12–/–), thus indicating that absence of metalloelastase does not produce a global failure of the upregulation of inflammatory mediators. Only the wild-type mice demonstrated an increase in whole-lung tumor necrosis factor-
and late release of pulmonary- and activation-regulated chemokine. Both Th1- and Th2-attracting chemokines were induced, but the resulting effect was increased chemotactic activity of Th2 cells and not of Th1 cells. Diesel induced a late increase in the expression of the Th1-associated CXC receptor 3 and CC receptor 5. Upregulation of T cell CXC receptor 3 was not associated with increased migration to its ligands. The authors conclude that diesel, even in the absence of allergen, amplifies Th2 immune response and that it also increases late Th1-associated chemoreceptor expression.