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Patients with chronic obstructive pulmonary disease (COPD) often suffer other concomitant disorders, such as cardiovascular diseases and metabolic disorders, that influence significantly (and independently of lung function) their health status and prognosis. Thus, COPD is not a single organ condition, and disturbances of a complex network of interorgan connected responses occur and modulate the natural history of the disease. Here, we propose a novel hypothesis that considers a vascularly connected network with (1) the lungs as the main external sensor of the system and a major source of "danger signals"; (2) the endothelium as an internal sensor of the system (also a potential target tissue); and (3) two key responding elements, bone marrow and adipose tissue, which produce both inflammatory and repair signals. According to the model, the development of COPD, and associated multimorbidities (here we focus on cardiovascular disease as an important example), depend on the manner in which the vascular connected network responds, adapts, or fails to adapt (dictated by the genetic and epigenetic background of the individual) to the inhalation of particles and gases, mainly in cigarette smoke. The caveats and limitations of the hypothesis, as well as the experimental and clinical research needed to test and explore the proposed model, are also briefly discussed.

Rationale: Inflammation and oxidative stress contribute to muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD). Oxidantscontainedin cigarette smoke(CS) induceadverse effects on tissues through oxidative phenomena. Objectives: To explore oxidative stress and inflammation in quadricepsofhumansmokersandindiaphragmandlimbmusclesofguinea pigs chronically exposed to CS. Methods: Muscle function, protein oxidation and nitration, antioxidants, oxidized proteins, inflammation, creatine kinase activity, and lung and muscle structures were investigated in vastus lateralis of smokers, patients with COPD, and healthy control subjects and in diaphragmandgastrocnemiusofCS-exposedguineapigsat3,4,and 6 months. Measurements and Main Results: Compared with control subjects, quadriceps muscle force was mildly but significantly reduced in smokers; protein oxidation levels were increased in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed animals; glycolytic enzymes, creatine kinase, carbonic anydrase-3, and contractile proteins were significantly more carbonylated in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed guinea pigs. Chronic CS exposure induced no significant rise in muscle inflammation in either smokers or rodents. Muscle creatine kinase activity was reduced only in patients with COPD and in both diaphragm and gastrocnemius of CS-exposed animals. Guinea pigs developed bronchiolar abnormalities at 4 months of exposure and thereafter. Conclusions: CS exerts direct oxidative modifications on muscle proteins, without inducing any significant rise in muscle inflammation. The oxidative damage to muscle proteins, which precedes the characteristic respiratory changes, may contribute to muscle loss and dysfunction in smokers and patients with COPD.

Sildenafil, a phosphodiesterase-5 inhibitor, could be useful for treating pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD). However, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange in this condition.To assess the acute hemodynamic and gas exchange effects of sildenafil in patients with COPD-associated PH.We conducted a randomized, dose comparison trial in 20 patients with COPD-associated PH. Eleven patients were assigned to 20 mg, and 9 patients to 40 mg, of sildenafil. Pulmonary hemodynamics and gas exchange, including ventilation-perfusion (V(A)/Q) relationships, were assessed at rest and during constant-work rate exercise, before and 1 hour after sildenafil administration.Both sildenafil doses reduced the mean pulmonary arterial pressure (PAP) at rest and during exercise, without differences between them. Overall, PAP decreased -6 mm Hg (95% confidence interval [95% CI], -7 to -4) at rest and -11 mm Hg (95% CI, -14 to -8) during exercise. After sildenafil, Pa(O(2)) decreased -6 mm Hg (95% CI, -8 to -4) at rest because of increased perfusion in units with low V(A)/Q ratio, without differences between doses. No change in Pa(O(2)) (95% CI, -3 to 0.2 mm Hg) or V(A)/Q relationships occurred during exercise after sildenafil. Changes induced by sildenafil in Pa(O(2)) and V(A)/Q distributions at rest correlated with their respective values at baseline.In patients with COPD-associated PH, sildenafil improves pulmonary hemodynamics at rest and during exercise. This effect is accompanied by the inhibition of hypoxic vasoconstriction, which impairs arterial oxygenation at rest. The use of sildenafil in COPD should be done cautiously and under close monitoring of blood gases. Clinical trial registered with www.clinicaltrials.gov (NCT00491803).

Short-acting beta(2)-agonists are one of the mainstays of bronchodilator strategy for exacerbations of chronic obstructive pulmonary disease (COPD). The assessment of pulmonary gas exchange after salbutamol in COPD severe exacerbations remains unknown.We investigated whether the effects of nebulized salbutamol during COPD severe exacerbations are associated with further deterioration of pulmonary gas exchange.We examined patients with severe COPD when hospitalized for exacerbation (n = 9), and while in stable convalescence.We assessed spirometry, arterial blood gases, systemic hemodynamics, and V/Q relationships 30 and 90 minutes after administration of 5.0 mg salbutamol. At exacerbation, compared with baseline, 30 minutes after salbutamol administration, cardiac output (Q) increased (from 6.5 +/- [SEM] 0.4 to 7.3 +/- 0.5 L . min(-1)) (p0.03) alone, without inducing changes in gas exchange indices. When in convalescence, compared with baseline, 30 minutes after salbutamol, there was an increase in Q (from 5.7 +/- 0.5 to 7.0 +/- 0.6 L . min(-1)) and Vo(2) (from 211 +/- 12 to 232 +/- 11 ml . min(-1)) (p0.002 each), whereas Pa(O(2)) decreased (from 71 +/- 4 to 63 +/- 3 mm Hg) and alveolar-arterial Po(2) difference increased due to increased perfusion of low-V/Q-ratio regions (from 4.5 +/- 2.6 to 9.6 +/- 4.1% of Q) (p0.05); Sa(O(2)) (93 +/- 2%) and Pa(CO(2)) (43 +/- 2 mm Hg) remained unchanged. This deleterious gas exchange response persisted at 90 minutes.At exacerbation, salbutamol does not aggravate pulmonary gas exchange abnormalities. When in convalescence, however, baseline lung function improvement was associated with a detrimental gas exchange response to salbutamol, resulting in further V/Q imbalance and small decreases in Pa(O(2)) compounded by small increases in Q and Vo(2).

Chronic obstructive pulmonary disease (COPD) is associated with structural and functional changes in the pulmonary circulation that commence at an early stage. To investigate whether vascular endothelial growth factor (VEGF) might be implicated as a mediator in COPD-associated pulmonary vascular changes, we studied surgical specimens obtained from 19 nonsmokers, 21 smokers with normal lung function, 28 patients with moderate COPD, and 10 patients with severe emphysema. The expression of VEGF in pulmonary muscular arteries was evaluated by immunohistochemistry, its protein content in lung tissue by Western blot analysis, and VEGF mRNA and its isoforms were analyzed by reverse transcription-polymerase chain reaction. The immunohistochemical expression of VEGF was increased in pulmonary arteries of smokers (median, 68% [interquartile range, 60-88]) and patients with moderate COPD (77% [63-82]), compared with nonsmokers (53% [40-63]) (p0.05 each). The expression of VEGF in smooth muscle cells correlated with the thickness of the vessel wall (r = 0.38, p0.01). VEGF protein content in lung tissue was reduced in severe emphysema, where reverse transcription-polymerase chain reaction demonstrated a lower proportion of the VEGF189 isoform. In conclusion, the expression of VEGF varies according to the severity of COPD and might be involved in the pathogenesis of pulmonary vascular remodeling at early stages of the disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available.To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions.Investigations were performed in human lung tissue from patients with COPD, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours per day, 5 days per week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from six cigarettes per day for 3 months, 5 days per week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time polymerase chain reaction and Western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, and alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation, and apoptosis have been done.The functionally essential sGC β1-subunit was down-regulated in patients with COPD and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma, and inhibited adhesion of CS-stimulated neutrophils.The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.

The present study was undertaken to test whether endurance training in patients with COPD, along with enhancement of muscle bioenergetics, decreases muscle redox capacity as a result of recurrent episodes of cell hypoxia induced by high intensity exercise sessions. Seventeen patients with COPD (FEV 1 , 38 � 4% pred; Pa O2 , 69 � 2.7 mm Hg; Pa CO2 ,42 � 1.7 mm Hg) and five agematched control subjects (C) were studied pretraining and posttraining. Reduced (GSH) and oxidized (GSSG) glutathione, lipid peroxidation, and gamma-glutamyl cysteine synthase heavy subunit chain mRNA expression ( � GCS-HS mRNA) were measured in the vastus lateralis. Pretraining redox status at rest and after moderate (40% Wpeak) constant-work rate exercise were similar between groups. After training ( � Wpeak, 27 � 7% and 37 � 18%, COPD and C, respectively) (p � 0.05 each), GSSG levels increased only in patients with COPD (from 0.7 � 0.08 to 1.0 � 0.15 nmol/ mg protein, p � 0.05) with maintenance of GSH levels, whereas GSH markedly increased in C (from 4.6 � 1.03 to 8.7 � 0.41 nmol/

Cigarette smoking has been associated with alterations in the structure and endothelial function of pulmonary arteries. Nitric oxide (NO) and endothelin-1 are endothelium-derived mediators with opposite effects on vascular tone and cell growth. To investigate whether cigarette smoking could induce changes in the synthesis of these mediators in pulmonary arteries, we compared the expression of both endothelial NO synthase (eNOS) and endothelin-1 in the lungs of smokers with that in nonsmokers. Lung tissue samples of 23 smokers and nine nonsmokers were studied. Expression of eNOS and endothelin-1 in pulmonary artery endothelium was evaluated by immunohistochemistry. In protein extracts of lung tissue, the content of eNOS protein was assessed by Western blot analysis and that of endothelin-1 by radioimmunoassay. The immunohistochemical expression of eNOS in arterial endothelium and the eNOS protein content in lung tissue were lower in the smokers than in the nonsmokers. No differences were shown in cell expression and protein content of endothelin-1 between both groups. We conclude that cigarette smoking is associated with reduced expression of eNOS in pulmonary arteries. The diminished synthesis of nitric oxide may contribute to the alterations in the structure and endothelial function of pulmonary vessels in cigarette-smoke-induced respiratory disease.

Inhalational challenges with inflammatory mediators may provoke lung function disturbances similar to those shown in spontaneous acute asthma. Cysteinyl leukotrienes (CysLTs) have recently been established as mediators of bronchoconstriction in asthma but their effects on pulmonary gas exchange in asthma have not been assessed. We therefore investigated the effects of leukotriene D(4) (LTD(4)) challenge resulting in a significant decrease in FEV(1) (mean +/- SE, by 32 +/- 3%) in 13 nonsmoking, mild asthmatics. Respiratory system resistance (Rrs), and respiratory and inert gases were measured before and immediately after, and at 15 and 45 min after challenge. After bronchoprovocation, Rrs increased (by 106 +/- 12%), Pa(O(2)) decreased (by 25 +/- 4 mm Hg), and ventilation-perfusion distributions moderately to severely deteriorated, as shown by increases in the dispersions of pulmonary blood flow (Log SDQ, by 59 +/- 12%) and alveolar ventilation (Log SDV, by 65 +/- 20%) (p0.05 each). Sputum eosinophils (p0.05) and urinary LTE(4) (p0.005) increased after challenge. Despite the lack of mathematical correlations between spirometric and Rrs changes and gas exchange indices, the pattern of improvement of the functional variables after challenge ran in parallel. These findings support the evidence that CysLTs, in addition to being potent bronchoconstrictors, also provoke profound disturbances of pulmonary gas exchange in asthma.

To assess the effects on bronchial responsiveness of nebulized glutathione (GSH), one of the most efficient scavengers of oxidant substances in the airways, we studied eight patients with mild asthma (FEV1, 88 +/- 11% predicted [SD]) in a randomized, double-blind, cross-over, placebo-controlled fashion. Bronchial challenge was measured using both FEV1 and total pulmonary resistance (Rrs) by the forced oscillation technique. Patients received nebulized GSH (600 mg with 4 ml of 0.9% sodium chloride) or placebo (identical saline solution) over a period of 25 min, 1 wk apart. Placebo provoked subclinical mild bronchoconstriction (changes from baseline: FEV1, -1%; Rrs, +17%); by contrast, GSH caused major airway narrowing (changes from baseline: FEV1, -19%; Rrs, +61%) and induced cough (four patients) or breathlessness (three patients). Differences between placebo and GSH after challenge were also noticeable in both FEV1 (p = 0.03) and Rrs (p = 0.02). Neither osmolarity (660 mosm.kg-1) nor pH (3.0) of the GSH solution accounted for these effects. Nebulized salbutamol (5.0 mg) given before the GSH challenge blocked GSH-induced bronchoconstriction. Furthermore, GSH-induced FEV1 falls were inversely correlated with metabisulfite bronchoprovocation (provocative dose [PD20], 1.49 +/- 1.83 mumol) but not with methacholine challenge. The detrimental effects of nebulized GSH on the airway bronchial tone in patients with mild asthma strongly suggests bronchoconstriction provoked by sulfite formation.

Arterial oxygen tension (PaO2) is known to decrease with age, and this is accompanied by a number of changes in mechanical properties of the lungs, including loss of elastic recoil and increase in closing volume. The changes in respiratory mechanics with age could induce greater ventilation/perfusion (VA/Q) mismatch and thus explain the decrease in PaO2. In 64 normal subjects aged 18 to 71 yr (lifetime nonsmokers with normal spirometry), we measured VA/Q inequality and arterial respiratory blood gases (PaO2 and PaCO2) at rest in the seated position. VA/Q mismatch, represented by the second moments of the blood flow and ventilation distributions (log SDQ and log SDV) increased with age, but only slightly (mean log SDQ was 0.36 at age 20 yr and 0.47 at age 70 yr). PaO2 fell by a correspondingly small amount of 6 mm Hg. Previously established upper 95% confidence limits for log SDQ (0.60) and log SDV (0.65) in subjects at age 20 yr were confirmed. At age 70 yr, the upper limits of reference for log SDQ are 0.70 and for log SDV 0.75. The study shows that an increased alveolar-arterial O2 gradient with age is due to VA/Q inequality rather than to shunting.

The equation proposed by Cotes and coworkers is currently considered as the most acceptable to correct carbon monoxide diffusing capacity (DLCO) for hemoglobin concentration [Hb] by both the American Thoracic Society (ATS) and the European Respiratory Society (ERS) guidelines for standardization of DLCO. In a previous study on 24 anemic patients undergoing bone marrow transplantation (1), we found that DLCO is underestimated using the equation of Cotes and coworkers. To further explore this finding, 28 anemic patients ([Hb] = 8.2 +/- 1.0 (SD) g/dl) with chronic renal failure were prospectively studied during the recovery period of anemia (5.4 +/- 3.5 mo). In all 28 subjects, the slope deltaDLCO/delta[Hb] computed as ratio of overall change in DLCO to overall change in [Hb] throughout the study period was 1.40 +/- 0.72 ml CO/min/mm Hg/g/dl. The individual relationship between measured DLCO and [Hb] closely fitted a simple linear regression. The resulting equations for adjustment of DLCO (DLCOadj) to a standard [Hb] of 14.6 g/dl for men and 13.4 g/dl for women are: [equations: see text]. The present adjustment function for DLCO is linear and independent of the observed DLCO values, whereas the formulas previously proposed are curvilinear, DLCO correction varying with the measured DLCO values. For a measured DLCO of 15 ml CO/min/mm Hg and [Hb] ranging from 7 to 12 g/dl, the present DLCO adjustment is higher (by 2.7 ml CO/min/mm Hg, on average) than that proposed by Cotes and coworkers. This difference appears to be relevant for a precise interpretation of DLCO in patients with normocytic anemia in different clinical conditions.

Inhaled platelet-activating factor (PAF) provokes considerable pulmonary gas exchange disturbances in normal man and in patients with mild asthma, similar to those observed in acute severe asthma. To further examine the mechanisms involved in PAF-induced ventilation-perfusion (VA/Q) mismatch, eight healthy, non-atopic, nonsmoking subjects were studied after administration of PAF aerosol (24 micrograms). They had been previously treated with inhaled salbutamol (300 micrograms) in a randomized, double-blind, cross-over, placebo-controlled design. After placebo, PAF provoked a fall in total arterial white cell count with a rebound leukocytosis. As shown in a previous study, an overall index of VA/Q inequality (DISP R-E*, 1.64 +/- 0.10) showed a threefold increase (P0.006) that accounted for the increase (79%) in AaPO2 (p0.04) after PAF, while the respiratory system resistance (Rrs) rose by 16% (p0.02). In contrast, after pretreatment with salbutamol inhaled PAF had no effects on pulmonary gas exchange, Rrs, or white cell count; facial flushing and cough were also hindered. The results are consistent with the hypothesis that salbutamol inhibits PAF-induced venoconstriction in both the airway and pulmonary microcirculation.

Morphologic changes in pulmonary muscular arteries may modify the mechanisms that regulate the pulmonary vascular tone and contribute to maintaining an adequate ventilation-perfusion (VA/Q) matching in patients with chronic obstructive pulmonary disease (COPD). To analyze the relationships between the abnormalities of pulmonary muscular arteries and the degree of VA/Q inequality, and to assess the effect of these abnormalities on the changes in VA/Q relationships induced by oxygen breathing, we studied a group of patients with mild COPD undergoing resective lung surgery. According to the degree of airflow obstruction and the increase in VA/Q mismatch produced by 100% O2 breathing (delta logSD Q), patients were divided into three groups: (A) patients with normal lung function, (B) patients with airflow obstruction and a high response to oxygen (delta logSD Q > 0.4), and (C) patients with airflow obstruction and a low response to oxygen (delta logSD Q < 0.4). Pulmonary arteries in Groups B and C showed narrower lumens and thicker walls than in Group A. These morphologic changes were produced mainly by an enlargement of the intimal layer and were more pronounced in Group C than in Group B. The assessment of intimal area as a function of artery diameter showed that the increase in intima in Group C took place predominantly in arteries with small diameters (< 500 microns). The mean intimal area on each subject correlated with both the PaO2 value (r = -0.46, p < 0.05) and the overall index of VA/Q mismatching (r = 0.51, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The wreckage of the oil tanker Prestige in November 2002 produced heavy contamination off the coast of Galicia, Spain.To evaluate the prevalence of respiratory symptoms in local fishermen more than 1 year after having participated in clean-up work.Questionnaires including qualitative and quantitative information about clean-up activities and respiratory symptoms were distributed among associates of 38 fishermen's cooperatives. Both postal and telephone follow-up was performed. The association between participation in clean-up work and respiratory symptoms was evaluated using multiple logistic regression analyses, adjusted for sex, age, and smoking status.Between January 2004 and February 2005, data were obtained from 6,780 fishermen (response rate, 76%). Sixty-three percent had participated in clean-up operations. Lower respiratory tract symptoms (LRTS) were more prevalent in clean-up workers: odds ratio (OR), 1.73; 95% confidence interval (CI), 1.54-1.94. This association was consistent for men and women, for different fishermen's cooperatives, and for different types of respiratory symptoms, and remained after excluding those who reported anxiety or believed that the oil spill had affected their health (OR, 1.57; 95% CI, 1.37-1.80). The risk of LRTS increased with the number of exposed days, exposed hours per day, and number of activities (linear trend, P0.0001). The excess risk of LRTS decreased when more time had elapsed since last exposure: OR, 2.33, 1.69, and 1.24 for less than 14 months, 14-20 months, and more than 20 months, respectively.Participation in clean-up work of oil spills may result in prolonged respiratory symptoms that last 1 to 2 years after exposure.

Endothelial dysfunction and intimal thickening have been shown in pulmonary arteries (PA) of patients with mild chronic obstructive pulmonary disease (COPD). To investigate whether an inflammatory process related to tobacco smoking might be involved in the development of pulmonary vascular abnormalities in COPD, we characterized the inflammatory cell infiltrate and the endothelium-dependent relaxation in PA of 39 patients who underwent lung resection, divided into three groups: "nonsmokers" (n = 7); "smokers," with normal lung function (n = 12); and "COPD" (n = 20). Endothelium-dependent relaxation was assessed in vitro by exposing PA rings to adenosine diphosphate (ADP). Inflammatory cell types were identified by immunohistochemistry. PA of COPD patients developed lower relaxation in response to ADP than nonsmokers and smokers. The number of inflammatory cells was increased in PA of COPD compared with the other two groups. This cell infiltrate was largely constituted by T lymphocytes. The CD8(+) T-cell subset was increased in both smokers and COPD compared with nonsmokers, yielding a reduction of the CD4(+)/CD8(+) ratio. The intensity of the inflammatory infiltrate correlated with both the endothelium-dependent relaxation and the intimal thickness. We conclude that cigarette smoking induces a CD8(+) T-lymphocyte infiltrate in PA, which is associated with the impairment of the vessel's structure and function, suggesting the potential involvement of an inflammatory process in the pathogenesis of pulmonary vascular abnormalities in the early stage of COPD.

To investigate whether salbutamol inhibits platelet-activating factor (PAF)-induced neutrophil sequestration in the lungs, we studied eight nonatopic, nonsmoking, healthy subjects (six men; aged 27.0 +/- 1.5 (SE) yr) with PAF-induced bronchial response. Prior to PAF challenge (24 micrograms), they inhaled either salbutamol (300 micrograms) or placebo in a randomized, double-blind, crossover manner two weeks apart. Respiratory system resistance (Rrs), arterial blood gases, and neutrophil counts were measured 4, 8, 12 and 30 min after PAF. Neutrophil kinetics in the lungs were assessed by tracking autologous 99mTc-erythrocytes and 111in-neutrophils. Compared with salbutamol, arterial blood neutrophil counts fell (p < 0.04) maximally at 4 min after PAF, followed by a mild rebound neutrophilia, whereas Rrs increased (p < 0.01) and Pao2 decreased (p < 0.05) at 4 min only. The intrapulmonary activity of 111in-neutrophils after pretreatment with placebo was higher compared with salbutamol (1.98 +/- 0.15 versus 1.33 +/- 0.23 cps/mCi/pixel) (p < 0.01) although both their initial sequestration (first-pass) and subsequent washout were not significantly different. Inhaled salbutamol blocks pulmonary neutrophil sequestration and lung function abnormalities following PAF challenge in humans.