Authors: Argyris Tzouvelekis; Ioannis Kotsianidis; Paschalis Steiropoulos; Demosthenes Bouros

Author: Shawn D. Aaron

Authors: Peter Kardos; Marion Wencker; Thomas Glaab; Claus Vogelmeier

Authors: Claus Vogelmeier; Robert Bals

Authors: Vallerie V. McLaughlin; Richard Channick

Authors: Geraldo Lorenzi-Filho; Luciano F. Drager

Authors: Klaus F. Rabe; Bianca Beghé; Fabrizio Luppi; Leonardo M. Fabbri

Authors: Coen A. C. Ottenheijm; Leo M. A. Heunks; P. N. Richard Dekhuijzen

Inspiratory muscle weakness in patients with chronic obstructive pulmonary disease (COPD) is of major clinical relevance; maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered of pathologic nature. Although the fiber-type shift toward oxidative type I fibers in COPD diaphragm is regarded as beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single-fiber level is associated with loss of myosin content. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. The current Pulmonary Perspective postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force-generating capacity of diaphragm fibers in patients with COPD. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients do not appear to be limited in their daily-life activities. Therefore, investigating in vivo diaphragm function in mild to moderate COPD should be the focus of future research. Treatment of diaphragm dysfunction in COPD is complex because its etiology is unclear, but recent findings show promise for the use of proteasome inhibitors in syndromes associated with muscle wasting, such as the diaphragm in COPD.

Authors: Pierre Camateros; Meiyo Tamaoka; Muhannad Hassan; Rafael Marino; Jacques Moisan; Dominique Marion; Marie-Christine Guiot; James G. Martin; Danuta Radzioch

Rationale: Allergic asthma is a heterogeneous disease, the pathology of which is a result of improper immune responses to innocuous antigens. We and others have previously shown that one of the Toll-like receptor (TLR)-7/8 ligands, the synthetic compound S28463 (resiquimod, R-848), is able to inhibit acute allergic asthma in mice.

Objectives: Given that the efficiency of this pharmacologic compound against the smooth muscle mass increase and goblet cell hyperplasia that are characteristic of chronic allergic asthma has not been previously assessed, we investigated the ability of this compound to prevent these aspects of chronic airway remodeling.

Methods: The impact of S28463 treatment was assessed in a Brown Norway rat model of chronic asthma by histologic, morphometric, and molecular techniques.

Measurements and Main Results: We demonstrate that treatment with S28463 is able to prevent the development of goblet cell hyperplasia and increases in airway smooth muscle mass, and that this effect is at least partially mediated by inhibiting proliferation of goblet and smooth muscle cells, respectively. Furthermore, we show that the abrogation of airway remodeling is preceded by inhibition of the inflammatory reaction normally occurring in response to allergen challenge in sensitized animals. This inhibition was associated with a reduction of both helper T cell type 1 and type 2 cytokine protein expression in the lungs, demonstrating the potent antiinflammatory effect of this pharmaceutical compound in the context of allergic reactions.

Conclusions: Taken together, our results indicate great potential for the use of S28463 as an antiinflammatory therapeutic agent for the management of chronic asthma.

Authors: Patricia Dillard; Rick A. Wetsel; Scott M. Drouin

Rationale: The factors that control the secretion of epithelial mucins are essential to understanding obstructive airway diseases such as asthma. Although the complement anaphylatoxin C3a and its receptor have been shown to promote many features of allergic lung inflammation, the contribution to mucin expression has not been elucidated.

Objectives: To determine if the C3a receptor with its ligand regulates airway epithelial mucin production.

Methods: Mice deficient in the C3a receptor were examined in a model of allergic airway disease for the presence of goblet cells and the gel-forming secreted mucin Muc5ac.

Measurements and Main Results: Lungs from antigen-challenged C3a receptor–deficient mice revealed a dramatic decrease in goblet cells and Muc5ac compared with challenged wild-type control animals. These differences were dependent on C3a binding to its receptor since intranasal challenge with C3a induced the formation of goblet cells only in wild-type but not C3a receptor–deficient mice. Increased numbers of goblet cells were also found in C3a-stimulated RAG-1–deficient mice demonstrating a mechanism independent of T lymphocytes and Th2 cytokines, mediators which have been shown to regulate mucin expression. A direct physiological role for C3a in these models was further demonstrated in cultures of airway epithelial Clara cells, which not only express the C3a receptor but also produce Muc5ac in response to C3a.

Conclusions: These studies identify a novel C3a receptor–dependent mechanism in the development of airway epithelial goblet cells and regulation of Muc5ac production and implicate C3a as a mediator of airway obstruction in asthma.

Authors: Ramsey Sabit; Charlotte E. Bolton; Peter H. Edwards; Rebecca J. Pettit; William D. Evans; Carmel M. McEniery; Ian B. Wilkinson; John R. Cockcroft; Dennis J. Shale

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular events and osteoporosis. Increased arterial stiffness is an independent predictor of cardiovascular disease.

Objectives: We tested the hypothesis that patients with COPD would have increased arterial stiffness, which would be associated with osteoporosis and systemic inflammation.

Methods: We studied 75 clinically stable patients with a range of severity of airway obstruction and 42 healthy smoker or ex-smoker control subjects, free of cardiovascular disease. All subjects underwent spirometry, measurement of aortic pulse wave velocity (PWV) and augmentation index, dual-energy X-ray absorptiometry, and blood sampling for inflammatory mediators.

Measurements and Main Results: Mean (SD) aortic PWV was greater in patients, 11.4 (2.7) m/s, than in control subjects, 8.95 (1.7) m/s, p < 0.0001. Inflammatory mediators and augmentation index were also greater in patients. Patients with osteoporosis at the hip had a greater aortic PWV, 13.1 (1.8) m/s, than those without, 11.2 (2.7) m/s, p < 0.05. In patients, aortic PWV was related to age (r = 0.63, p < 0.0001) and log10 IL-6 (r = 0.31, p < 0.01), and inversely to FEV1 (r = –0.34, p < 0.01). The strongest predictors of aortic PWV in all subjects were age (p < 0.0001), percent predicted FEV1 (p < 0.05), mean arterial pressure (p < 0.05), and log10 IL-6 (p < 0.05).

Conclusions: Increased arterial stiffness was related to the severity of airflow obstruction and may be a factor in the excess risk for cardiovascular disease in COPD. The increased aortic PWV in patients with osteoporosis and the association with systemic inflammation suggest that age-related bone and vascular changes occur prematurely in COPD.

Authors: Jesús Sancho; Emilio Servera; Juan Díaz; Julio Marín

Rationale: In patients with neuromuscular diseases, a chest infection is associated with a reduction in respiratory muscle function that may result in decreased cough effectiveness.

Objectives: To determine if a clinical or functional parameter in patients with amyotrophic lateral sclerosis (ALS) in a stable condition could predict spontaneous cough ineffectiveness during a respiratory tract infection.

Methods: Forty consecutive patients with ALS referred to our Respiratory Care Unit were studied during a one-year follow-up.

Measurements and Main Results: FEV1, FVC, FEV1/FVC, peak cough flow (PCF), peak velocity time (PVT), maximum inspiratory and expiratory pressures, and bulbar dysfunction evaluation using the Norris scale bulbar subscore (NBS). A total of 26 patients (65%) had spontaneous cough ineffectiveness during a respiratory tract infection. The best variables to predict nonassisted cough during a respiratory tract infection were NBS (p < 0.01) with a cutoff point of 29 (sensitivity, 0.89; specificity, 0.90; positive predicted value, 0.88; negative predictive value, 0.87), PCF (p < 0.001) with a cutoff point of 4.25 L/s (sensitivity, 0.74; specificity, 0.85; positive predictive value, 0.71; negative predictive value, 0.85), and PCF/PVT (p < 0.001) with a cutoff point of 28.88 L/s² (sensitivity, 0.77; specificity, 0.96; positive predictive value, 0.91; negative predictive value, 0.89).

Conclusions: In patients with stable ALS, bulbar dysfunction (NBS < 29), PCF (< 4.25 L/s), and PCF/PVT (< 28.88 L/s²) could predict the risk of ineffective spontaneous cough during a respiratory tract infection.

Authors: Anastasia Anthi; Roberto F. Machado; Maria L. Jison; Angelo M. Taveira-DaSilva; Lewis J. Rubin; Lori Hunter; Christian J. Hunter; Wynona Coles; James Nichols; Nilo A. Avila; Vandana Sachdev; Clara C. Chen; Mark T. Gladwin

Rationale: Although pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) associated with high mortality, there exist few data characterizing hemodynamics and cardiopulmonary function in this population.

Objectives: To characterize hemodynamics and cardiopulmonary function in patients with SCD with and without PH.

Methods: Patients with SCD with PH (n = 26) were compared with control subjects with SCD but without PH (n = 17), matched for age, hemoglobin levels, and fetal hemoglobin levels.

Measurements and Main Results: Upon catheterization, 54% of the patients with PH had pulmonary arterial hypertension, and 46% had pulmonary venous hypertension. When compared with control subjects, patients with PH exhibited lower six-minute-walk distance (435 ± 31 vs. 320 ± 20 m, p = 0.002) and oxygen consumption (50 ± 3% vs. 41 ± 2% of predicted, p = 0.02), and also had mild restrictive lung disease and more perfusion abnormalities on radionuclide lung scans. The six-minute-walk distance in this population inversely correlated with tricuspid regurgitant jet velocity (r = −0.55, p < 0.001), and mean pulmonary artery pressure (r = −0.57, p < 0.001), and directly correlated with maximal oxygen consumption (r = 0.49, p = 0.004), even after adjustment for hemoglobin, supporting an independent contribution of increasing pulmonary artery pressures to loss of exercise capacity.

Conclusions: Patients with SCD-associated PH have both pulmonary arterial and venous PH associated with severe limitations in exercise capacity, likely compounded by interstitial lung fibrosis and severe anemia. These data support the use of the six-minute-walk distance as an index of PH and cardiopulmonary function in patients with SCD.

Authors: Laimute Taraseviciene-Stewart; Mark R. Nicolls; Donatas Kraskauskas; Robertas Scerbavicius; Nana Burns; Carlyne Cool; Kathy Wood; Jane E. Parr; Susan A. Boackle; Norbert F. Voelkel

Rationale: Severe pulmonary arterial hypertension (SPH) is a frequently lethal condition characterized by pulmonary vascular remodeling and right heart strain or failure. SPH is also often associated with autoimmune and collagen vascular disorders.

Objectives: To study the effects of T cells on the development of experimental SPH.

Methods: Athymic nude rats lacking T cells were treated with a single subcutaneous injection of vascular endothelial growth factor (VEGF) receptor blocker SU5416 (20 mg/kg) to induce pulmonary vascular endothelial cell apoptosis. Immunohistochemical analysis and IL-4 levels of the lung tissue were performed. Cell death and proliferation were assessed by Western blot and immunohistochemistry.

Measurements and Main Results: In contrast to SU5416-treated euthymic rats that develop SPH only in combination with chronic hypoxia, athymic nude rats developed SPH and vascular remodeling (similar to clinical SPH) at normoxic conditions as demonstrated by measurements of pulmonary artery pressure and right ventricle hypertrophy. Pulmonary arterioles became occluded with proliferating endothelial cells and were surrounded by mast cells, B cells, and macrophages. IL-4, proliferating cell nuclear antigen, and collagen type I levels were markedly increased in SU5416-treated athymic rat lungs. Antibody deposition was noted along the vascular endothelium in rats with SPH. Finally, protection from SPH was conferred by immune challenge with spleen cells from euthymic nude rats.

Conclusions: These studies demonstrate the importance of a complete, intact immune system in protecting against pulmonary angioproliferation in this new model of SPH as well as the importance of intact VEGF receptor signaling for lung endothelial cell homeostasis.

Authors: Vladimir Savransky; Ashika Nanayakkara; Jianguo Li; Shannon Bevans; Philip L. Smith; Annabelle Rodriguez; Vsevolod Y. Polotsky

Rationale: Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is associated with hyperlipidemia, atherosclerosis, and a high cardiovascular risk. A causal link between obstructive sleep apnea and atherosclerosis has not been established.

Objectives: The objective of the present study was to examine whether CIH may induce atherosclerosis in C57BL/6J mice.

Methods: Forty male C57BL/6J mice, 8 weeks of age, were fed either a high-cholesterol diet or a regular chow diet and subjected either to CIH or intermittent air (control conditions) for 12 weeks.

Measurements and Main Results: Nine of 10 mice simultaneously exposed to CIH and high-cholesterol diet developed atherosclerotic lesions in the aortic origin and descending aorta. In contrast, atherosclerosis was not observed in mice exposed to intermittent air and a high-cholesterol diet or in mice exposed to CIH and a regular diet. A high-cholesterol diet resulted in significant increases in serum total and low-density lipoprotein cholesterol levels and a decrease in high-density lipoprotein cholesterol. Compared with mice exposed to intermittent air and a high-cholesterol diet, combined exposure to CIH and a high-cholesterol diet resulted in marked progression of dyslipidemia with further increases in serum total cholesterol and low-density lipoprotein cholesterol (124 ± 4 vs. 106 ± 6 mg/dl; p < 0.05), a twofold increase in serum lipid peroxidation, and up-regulation of an important hepatic enzyme of lipoprotein secretion, stearoyl-coenzyme A desaturase-1.

Conclusions: CIH causes atherosclerosis in the presence of diet-induced dyslipidemia.

Authors: Rachel Stovold; Ian A. Forrest; Paul A. Corris; Desmond M. Murphy; Jaclyn A. Smith; Sam Decalmer; Gail E. Johnson; John H. Dark; Jeffrey P. Pearson; Chris Ward

Rationale: Human lung transplantation is a therapeutic option for selected patients with advanced cardiopulmonary disease, but long-term survival is limited by chronic rejection. Persistent acute rejection and gastric aspiration have been implicated as risk factors but there is little or no evidence to date that they are associated.

Objectives: We have tested the hypothesis that pepsin, a marker of gastric aspiration, is present in lung transplant recipients, and that high levels are associated with biopsy-diagnosed acute rejection and/or bronchiolitis obliterans syndrome.

Methods: Levels of bronchoalveolar lavage (BAL) pepsin were measured by ELISA in 36 lung transplant recipients, 4 normal volunteers, and 17 subjects with unexplained chronic cough.

Measurements and Main Results: Our primary finding was that, compared with control subjects, BAL pepsin levels were elevated in stable lung transplant recipients, subjects with acute rejection, and subjects with bronchiolitis obliterans syndrome. Our secondary finding was that the highest levels were found in recipients with acute vascular rejection grade  A2 (median, 11.2; range, 5.4 – 51.7 ng/ml; normal median, 1.1; range, 0–2.3 ng/ml; p = 0.004).

Conclusions: We have shown that elevated levels of pepsin, a biomarker of gastric aspiration, are consistently identified in the BAL of lung allografts. The highest levels were seen in patients with  grade A2 acute rejection. This provides further evidence supporting the possible role of aspiration in the development of overall allograft injury.

Authors: Nicole Beydon; Stephanie D. Davis; Enrico Lombardi; Julian L. Allen; Hubertus G. M. Arets; Paul Aurora; Hans Bisgaard; G. Michael Davis; Francine M. Ducharme; Howard Eigen; Monika Gappa; Claude Gaultier; Per M. Gustafsson; Graham L. Hall; Zoltán Hantos; Michael J. R. Healy; Marcus H. Jones; Bent Klug; Karin C. Lødrup Carlsen; Sheila A. McKenzie; Francçois Marchal; Oscar H. Mayer; Peter J. F. M. Merkus; Mohy G. Morris; Ellie Oostveen; J. Jane Pillow; Paul C. Seddon; Michael Silverman; Peter D. Sly; Janet Stocks; Robert S. Tepper; Daphna Vilozni; Nicola M. Wilson

Authors: Patrick K. Y. Goon; Timothy Watson; Gregory Y. H. Lip

Author: Ali El Solh