© 2003 American Thoracic Society
Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2002Division 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) Genetics (1) Epidemiology (3)
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)
Outcome (1) Workshops (1) Air Pollution (6) Air Pollution—General (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)
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—glutathione S-transferase (GST) M1, T1, P1, or heme oxygenase-1—had 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 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.
Takubo and coworkers (6) determined whether the level of
Risk Factors
Cellular, Molecular, and Anatomic Abnormalities
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- 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–modified 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 p21CIP1/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)-xL, an antiapopoptotic regulator, was highly expressed in macrophages from the smokers. In in vitro studies, hydrogen peroxide induced cytoplasmic expression of p21CIP1/WAF1 and failed to induce apoptosis. The authors conclude that p21CIP1/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
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-
To better define the role of tumor necrosis factor-
Lung Inflammation
Pathophysiologic and Radiologic Studies 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
Control of Breathing and Exercise
Respiratory Muscles 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 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
Theophylline.
Glucocorticoids. 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–salmeterol 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–control 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–response 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. 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-
Other Therapies In 12 patients with severe emphysema (FEV1, 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.
Outcome
Workshops
Air Pollution–General 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 (FEF25–75, -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 (PM2.5), 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
Pulmonary Hypertension Molecular and pathophysiologic mechanisms. The CX3E chemokine, fractalkine, is produced by endothelial cells, promotes leukocyte recruitment, and is unique because it exists both in a soluble form (chemotactic protein) and in a membrane-anchored form on endothelial cells (cell-adhesion molecule). To assess the role of fractalkine in the recruitment of cells to the lungs of patients with pulmonary hypertension, Balabanian and coworkers (56) studied seven patients with pulmonary arterial hypertension and eight patients with chronic thromboembolic pulmonary hypertension. The fractalkine receptor (CX3CR1) was upregulated in circulating T lymphocytes (mostly in the CD4+ subset) in patients with pulmonary arterial hypertension. The abnormal response of T lymphocytes to fractalkine was not secondary to high vascular pressure because it did not occur in patients with chronic thromboembolic hypertension. Concentrations of soluble fractalkine were higher in patients with pulmonary arterial hypertension than in patients with chronic thromboembolic hypertension and control subjects. Messenger RNA and the protein product of fractalkine were expressed in pulmonary artery endothelial cells of patients with pulmonary arterial hypertension. The authors conclude that inflammatory mechanisms involving the chemokine fractalkine and its receptor contribute to the injury of pulmonary arterial hypertension. An editorial commentary by Williams (57) accompanies this article. Endothelin-1 has been implicated in pulmonary hypertension because of its dual vasoconstrictor and mitogenic actions. The effects of endothelin-1 are mediated via two distinct receptors: endothelinA and endothelinB. Davie and coworkers (58) examined the distribution of these receptors in the pulmonary arteries, and studied their role in mediating the proliferative actions of endothelin-1. EndothelinB receptors were more frequent in the distal arteries than in the proximal arteries: 36% versus 3%. The density of receptors in distal arteries and lung parenchyma was twice as great in 22 patients with pulmonary hypertension than in 13 control subjects. Endothelin-1 stimulated DNA synthesis and attenuated the antiproliferative action of cicaprost and forskolin on pulmonary artery smooth muscle cells; these effects were mediated by both the endothelinA and endothelinB receptors. The stimulation of smooth muscle proliferation by serum was attenuated by inhibiting either the release of endothelin-1 (with phosphoramidon) or the action of endothelin-1 (with PD 145,065). Cicaprost inhibited the release of endothelin-1 from the smooth muscle cells and increased the intracellular concentration of cyclic AMP, whereas stimulation of the endothelinB receptor decreased the concentration of cyclic AMP. The authors conclude that the distributions of endothelinA and endothelinB receptors differ in human pulmonary arteries, and that both receptors promote the proliferation of smooth muscle cells and may contribute to vascular remodeling in pulmonary hypertension. The plexiform lesions of primary pulmonary hypertension contain macrophages and lymphocytes. Because RANTES (regulated upon activation, normal T cell expressed and secreted) is an important chemoattractant for monocytes and T cells, Dorfmuller and coworkers (59) determined whether this chemokine promotes cell recruitment in the lungs of patients with pulmonary hypertension. The expression of RANTES was eight times greater in lung samples from 10 patients with severe pulmonary hypertension than in the lungs of 7 control subjects. The major source of RANTES was the endothelial cells within the pulmonary artery wall. The expression of RANTES was associated with infiltrates of CD45+ inflammatory cells. The authors conclude that inflammatory mechanisms play a role in the natural history of pulmonary hypertension. In the hepatopulmonary syndrome, dilatation of pulmonary vessels is related to increased production of nitric oxide secondary to increased expression of inducible nitric oxide synthase by macrophages in the pulmonary vessels and less so to endothelial nitric oxide synthase. To investigate the role of translocation of gut bacteria in this syndrome, Rabiller and coworkers (60) administered a 5-week course of norfloxacin to rats with cirrhosis induced by ligation of the common bile duct. Norfloxacin decreased the incidence of gram-negative translocation from 70 to 0%, and it decreased the proportion of pulmonary microvessels containing more than 10 macrophages from 52 to 21%. Features of dilated pulmonary vessels (increased alveolar-to-arterial oxygen difference and cerebral uptake of labeled macro aggregates) were decreased to a level that fell between sham-operated rats and untreated cirrhotic rats. Norfloxacin decreased the expression and activity of inducible nitric oxide-synthase to normal, but not that of endothelial nitric oxide synthase. The authors conclude that norfloxacin decreases the severity of hepatopulmonary syndrome in cirrhotic rats by inhibiting translocation of gut bacteria and decreasing the production of nitric oxide by macrophages in pulmonary vessels. Reeves (61) recalls early studies on pulmonary vasoconstriction in cattle at high altitude.
Treatment. Prostacyclin requires a permanent central venous catheter, whereas the stable prostacyclin analog, treprostinil, can be given by subcutaneous infusion and has a longer half-life. In 470 patients with primary pulmonary hypertension, Simmonneau and coworkers (63) did a 12-week double-blind, placebo-controlled trial. Treprostinil increased the 6-minute walking distance by 16 m, and it improved dyspnea, signs and symptoms of pulmonary hypertension, and hemodynamics. Pain at the infusion site occurred in 85% of the treprostinil group, requiring premature discontinuation of therapy in 8% of patients. The authors conclude that chronic subcutaneous infusion of treprostinil is effective in patients with pulmonary hypertension and that its safety profile is acceptable. To determine the frequency and outcome of cardiopulmonary resuscitation in patients with pulmonary artery hypertension, Hoeper and coworkers (64) analyzed data on 3,130 patients from 17 referral centers in Europe and the United States. Circulatory arrest occurred in 513 patients and cardiopulmonary resuscitation was attempted in 132 (26%) of the patients. Resuscitation efforts were primarily unsuccessful in 104 patients (79%), and only 8 patients (6%) survived for more than 90 days. Hemodynamic measures within three months before the arrest did not predict outcome. The authors conclude that cardiopulmonary resuscitation is rarely successful in patients with pulmonary artery hypertension. In a rat model of pulmonary hypertension induced by left pneumonectomy and injection of monocrotaline, Nishimura and coworkers (65) studied the effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Compared with rats treated with placebo, rats treated with simvastatin from Days 5 to 35 after induction of pulmonary hypertension had a lower mean pulmonary artery pressure (27 versus 53 mm Hg) and less pulmonary vascular remodeling with neointimal formation (scores of 0.6 versus 2.0). Expression of the gene for nitric oxide synthase in lung endothelium was decreased in the mice treated with placebo, but the levels returned toward normal in the mice treated with simvastatin. The authors conclude that simvastatin attenuates pulmonary arterial hypertension, right-ventricular hypertrophy, and neointimal formation in pneumonectomized mice treated with monocrotaline. An editorial commentary by Rubin (66) accompanies this article. In a model of neonatal pulmonary hypertension in piglets, Shekerdemian and coworkers (67) studied the effect of intravenous sildenafil, a phosphodiesterase-5 inhibitor. Instilling human meconium into the trachea of piglets produced a 70% increase in pulmonary vascular resistance and a 100% increase in oxygenation index. Within 1 hour of commencing the infusion of sildenafil, pulmonary vascular resistance was reversed completely as compared with a 40% decrease in resistance after treatment with inhaled nitric oxide for 2 hours. Sildenafil also increased cardiac output by 30% without an adverse effect on oxygenation. The authors conclude that intravenous sildenafil is a selective and highly effective pulmonary vasodilator in piglets that have neonatal pulmonary hypertension. In a pulmonary perspective, Hoeper and colleagues (68) discuss new treatments for pulmonary arterial hypertension.
Thromboembolic Disorders
High Altitude A polymorphism of the gene for angiotensin-converting enzyme has been identified in which the presence (insertion, I allele), as opposed to the absence (deletion, D allele), of a fragment is associated with low tissue levels of the enzyme and enhanced performance in endurance athletes. An excess of the I allele has also been noted in South American natives living above 3,000 m. To determine whether this polymorphism is associated with oxygen saturation at high altitude, Woods and coworkers (71) studied 32 individuals who ascended to 5,000 m over 12 days and 40 individuals who ascended over 18.5 days. In the slow ascent group, oxygen saturation at rest and the fall in saturation with ascent were independent of genotype for angiotensin-converting enzyme. In the rapid ascent group, oxygen saturation was associated with genotype and saturation was relatively well sustained in the II subjects. The authors conclude that the insertion allele of the gene for angiotensin-converting enzyme is associated with maintenance of oxygen saturation during rapid ascent to high altitude.
Sickle Cell Disease
Lung Preservation To gain insight into pathophysiology of preservation and reperfusion injury during lung transplantation, de Perrot and coworkers (73) studied the kinetics of cytokine release in 18 consecutive patients undergoing bilateral lung transplantation. The levels of tumor necrosis factor-  , interferon- , interleukin-10, interleukin-12, and interleukin-18 were elevated during ischemia time. Interleukin-8 was predominantly increased after reperfusion; the level of interleukin-8 after two hours of reperfusion was correlated with the PO2/FIO2 ratio (r2 = 0.50), mean airway pressure (r2 = 0.60), APACHE score during the first 24 hours after surgery (r2 = 0.30), and length of stay in the intensive care unit. The authors conclude that the level of interleukin-8 is a significant predictor of graft function after lung transplantation. The current surgical procedures for lung transplantation do not reinstitute the systemic circulation of the graft. Nowak and coworkers (74) determined whether revascularization of the bronchial arteries would decrease ischemia–reperfusion injury in the transplanted lungs of dogs. Compared with control dogs, dogs undergoing either conventional lung transplantation or bronchial artery revascularization had higher levels of lactate dehydrogenase and carboxypeptidase M (a marker for type I pneumocytes) at 2 and 4 hours of reperfusion. The levels of alkaline phosphatase (a marker enzyme for type II pneumocytes) were higher in the animals undergoing conventional transplantation (60 IU per liter) than in animals undergoing bronchial revascularization (33 IU per liter) or in control animals (13.6 IU per liter). The level of angiotensin-converting enzyme (a marker for pulmonary endothelium) was also higher in the dogs undergoing conventional transplantation (1.4 IU per liter) than in dogs undergoing bronchial revascularization (0.35 IU per liter) or in control animals (0.06 IU per liter). The authors conclude that bronchial artery revascularization protects the pulmonary endothelium and type II pneumocytes after lung transplantation. ATP-sensitive potassium channel openers suppress the release of superoxide from neutrophils and play a central role in the suppression of reperfusion injury in cardiac muscle. To determine whether pinacidil, an ATP-sensitive potassium channel opener, attenuates ischemia–reperfusion injury of the lung, Fukuse and coworkers (75) used an ex vivo rat lung model. Heart–lung blocks preserved with pinacidil had lower shunt fraction, pulmonary artery pressure, and peak inspiratory pressure than did heart–lung blocks preserved with saline or with pinacidil combined with glibenclamide (a blocker of the channel opener). The concentrations of total adenine nucleotides and ATP in the lung after reperfusion were lower in the control group and in the glibenclamide group than in the fresh group. The control and glibenclamide groups displayed increased lipid peroxidation of the lungs after reperfusion, and decreased State 3 mitochondrial respiration and State 3/4 ratio of mitochondrial respiration. The authors conclude that ATP-sensitive potassium channel openers maintain mitochondrial respiratory function during lung preservation, prevent lipid peroxidation after reperfusion, and attenuate ischemia–reperfusion injury during lung preservation.
Patient Selection Deciding the right time to undertake lung transplantation in patients with cystic fibrosis is difficult, and the criteria used in guiding the decision are controversial. Mayer-Hamblett and coworkers (77) developed a mathematical model for predicting 2-year mortality using data on 14,572 patients in the National Patient Registry of the Cystic Fibrosis Foundation who were 6 years of age or older in 1996. Multivariate logistic regression revealed that age, height, FEV1, respiratory microbiology, number of hospitalizations for pulmonary exacerbations, and number of course of intravenous antibiotics in the home were significant predictors of 2-year mortality. When compared with the widely used criterion of an FEV1 of less than 30% of predicted, the mathematical model did not prove superior. The negative predictive value was 98% for the model and 97% for FEV1. The positive predictive value was 33% for the model and 28% for FEV1. Both the model and the FEV1 criterion will result in high rates of premature referral for lung transplantation. The authors conclude that a well-fitting mathematical model based on data from 14,572 patients with cystic fibrosis was not superior to the usual criterion of a FEV1 of less than 30% predicted in guiding decision on the best time to do lung transplantation. An editorial commentary by Noone and Egan (78) accompanies this article.
Obliterative Bronchiolitis
Activation of T cells, which may be involved in causing obliterative bronchiolitis, relies in part on the interaction between CD28 and its ligands, B7–1 and B7–2. In untreated rats with tracheal allografts (grafts from genetically dissimilar individuals of same species), Tikkanen and coworkers (80) found that expression of B7–2, but not of B7–1, peaked on the tenth day after transplantation. Upregulation of B7–2 was not seen in syngeneic grafts (grafts from a genetically identical rat). Administration of cytotoxic T lymphocyte antigen 4 immunoglobulin, which selectively blocks the costimulatory pathway of CD28 and its ligand B7–1, had no effect on the epithelial injury or the airway occlusion in the tracheal allografts; nor did it affect cytokine expression. Administration of a fusion protein that blocks both the interactions between CD28 and B7–1 and between CD28 and B7–2 delayed the epithelial injury and airway occlusion; it also decreased production of tumor necrosis factor-
To determine the role of growth factors in the pathogenesis of obliterative bronchiolitis in the mouse heterotopic trachea model, Aris and coworkers (81) implanted isografts and allografts in three sets of cyclosporine-treated mice. Compared with the isografts, the allografts had 1.5- to 5-fold increases in expression of transforming growth factor-ß, tumor necrosis factor-
Early detection. In a pulmonary perspective, Estenne and Hertz (83) discusses bronchiolitis obliterans after human lung transplantation.
Rejection
Immunology and Biochemistry
Physiology/Pathophysiology To determine whether the helper T lymphocytes in malignant pleural effusions undergo a shift to type 2 (Th2) helper responses, Oshikawa and coworkers (86) studied pleural fluid and sera from 17 patients with malignant effusions, 8 patients with tuberculous effusions, and 5 patients with congestive heart failure. CD4+ T cells isolated from the pleural fluid of the patients with malignant pleural effusions produced more interleukin-4 and interleukin-10 and less interferon- and interleukin-12 than did cells obtained from the other two patient groups. The concentration of ST2, which is preferentially expressed on Th2 effector cells but not on Th1 cells, was higher in the patients with malignant effusions than in the other two groups. The concentration of ST2 was positively correlated with the percentage of CD4+ T cells (r = 0.43) and inversely correlated with the concentration of interferon- (r = -0.42) in pleural fluid. The expression of messenger RNA of ST2 in CD4+ T cells was upregulated in malignant effusions. The authors conclude that CD4+ T cells in malignant pleural effusions shift to a type 2 (Th2) profile and produce soluble ST2 gene products. During the initial fibrinopurulent phase of a pleural loculation, fibrin bridges the visceral and parietal pleural surfaces. In rabbits with a pleural injury caused by tetracycline, Idell and coworkers (87) determined whether a single-chain urokinase plasminogen activator (alone or bound to its receptor) could prevent visceral-parietal adhesions. (This plasminogen activator enhances fibrinolytic activity and is relatively resistant to local inhibitors.) Urokinase bound to its receptor maintained fibrinolytic activity over 24 hours in the rabbits. When administered on its own into the pleura at 24 and 48 hours after intrapleural tetracycline, single-chain urokinase prevented the formation of adhesions. When bound to its receptor, administration of urokinase attenuated the formation of adhesions. At 72 hours after administration of tetracycline, antigenic, but not functional, evidence of the fibrinolytic agents persisted. The fibrinolytic agents did not cause local or systemic bleeding. The authors conclude that single-chain urokinase inhibits the formation of adhesions in rabbits with pleural injury caused by tetracycline. An editorial commentary by Antony (88) accompanies this article.
Clinical Manifestations
Treatment
Pleurodesis |
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CHRONIC OBSTRUCTIVE PULMONARY...
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.