TNFR1/phox interaction and TNFR1 mitochondrial translocation Thwart silica-induced pulmonary fibrosis.

Macrophages play a fundamental role in innate immunity and the pathogenesis of silicosis. Phagocytosis of silica particles is associated with the generation of reactive oxygen species (ROS), secretion of cytokines, such as TNF, and cell death that contribute to silica-induced lung disease. In macrophages, ROS production is executed primarily by activation of the NADPH oxidase (Phox) and by generation of mitochondrial ROS (mtROS); however, the relative contribution is unclear, and the effects on macrophage function and fate are unknown. In this study, we used primary human and mouse macrophages (C57BL/6, BALB/c, and p47(phox-/-)) and macrophage cell lines (RAW 264.7 and IC21) to investigate the contribution of Phox and mtROS to silica-induced lung injury. We demonstrate that reduced p47(phox) expression in IC21 macrophages is linked to enhanced mtROS generation, cardiolipin oxidation, and accumulation of cardiolipin hydrolysis products, culminating in cell death. mtROS production is also observed in p47(phox-/-) macrophages, and p47(phox-/-) mice exhibit increased inflammation and fibrosis in the lung following silica exposure. Silica induces interaction between TNFR1 and Phox in RAW 264.7 macrophages. Moreover, TNFR1 expression in mitochondria decreased mtROS production and increased RAW 264.7 macrophage survival to silica. These results identify TNFR1/Phox interaction as a key event in the pathogenesis of silicosis that prevents mtROS formation and reduces macrophage apoptosis.

Noninvasive ventilation for severely acidotic patients in respiratory intermediate care units : Precision medicine in intermediate care units.

BACKGROUND: Severe acidosis can cause noninvasive ventilation (NIV) failure in chronic obstructive pulmonary disease (COPD) patients with acute hypercapnic respiratory failure (AHRF). NIV is therefore contraindicated outside of intensive care units (ICUs) in these patients. Less is known about NIV failure in patients with acute cardiogenic pulmonary edema (ACPE) and obesity hypoventilation syndrome (OHS). Therefore, the objective of the present study was to compare NIV failure rates between patients with severe and non-severe acidosis admitted to a respiratory intermediate care unit (RICU) with AHRF resulting from ACPE, COPD or OHS. METHODS: We prospectively included acidotic patients admitted to seven RICUs, where they were provided NIV as an initial ventilatory support measure. The clinical characteristics, pH evolutions, hospitalization or RICU stay durations and NIV failure rates were compared between patients with a pH ≥ 7.25 and a pH < 7.25. Logistic regression analysis was performed to determine the independent risk factors contributing to NIV failure. RESULTS: We included 969 patients (240 with ACPE, 540 with COPD and 189 with OHS). The baseline rates of severe acidosis were similar among the groups (45 % in the ACPE group, 41 % in the COPD group, and 38 % in the OHS group). Most of the patients with severe acidosis had increased disease severity compared with those with non-severe acidosis: the APACHE II scores were 21 ± 7.2 and 19 ± 5.8 for the ACPE patients (p < 0.05), 20 ± 5.7 and 19 ± 5.1 for the COPD patients (p < 0.01) and 18 ± 5.9 and 17 ± 4.7 for the OHS patients, respectively (NS). The patients with severe acidosis also exhibited worse arterial blood gas parameters: the PaCO2 levels were 87 ± 22 and 70 ± 15 in the ACPE patients (p < 0.001), 87 ± 21 and 76 ± 14 in the COPD patients, and 83 ± 17 and 74 ± 14 in the OHS patients (NS)., respectively Further, the patients with severe acidosis required a longer duration to achieve pH normalization than those with non-severe acidosis (patients with a normalized pH after the first hour: ACPE, 8 % vs. 43 %, p < 0.001; COPD, 11 % vs. 43 %, p < 0.001; and OHS, 13 % vs. 51 %, p < 0.001), and they had longer RICU stays, particularly those in the COPD group (ACPE, 4 ± 3.1 vs. 3.6 ± 2.5, NS; COPD, 5.1 ± 3 vs. 3.6 ± 2.1, p < 0.001; and OHS, 4.3 ± 2.6 vs. 3.7 ± 3.2, NS). The NIV failure rates were similar between the patients with severe and non-severe acidosis in the three disease groups (ACPE, 16 % vs. 12 %; COPD, 7 % vs. 7 %; and OHS, 11 % vs. 4 %). No common predictive factor for NIV failure was identified among the groups. CONCLUSIONS: ACPE, COPD and OHS patients with AHRF and severe acidosis (pH ≤ 7.25) who are admitted to an RICU can be successfully treated with NIV in these units. These results may be used to determine precise RICU admission criteria.

Implementation of an Integrated Care Model for Frequent-Exacerbator COPD Patients: A Controlled Prospective Study.

INTRODUCTION: Frequent-exacerbator COPD (fe-COPD) associated with frequent hospital admissions have high morbidity, mortality and use of health resources. These patients should be managed in personalized integrated care models (ICM). Accordingly, we aimed to evaluate the long-term effectiveness of a fe-COPD ICM on emergency room (ER) visits, hospital admissions, days of hospitalization, mortality and improvement of health status. METHODS: Prospective-controlled study with analysis of a cohort of fe-COPD patients assigned to ICM and followed-up for maximally 7 years that were compared to a parallel cohort who received standard care. All patients had a confirmed diagnosis of COPD with a history of ≥2 hospital admissions due to exacerbations in the year before enrollment. The change in CAT score and mMRC dyspnea scale, hospital admissions, ER visits, days of hospitalization, and mortality were analyzed. RESULTS: 141 patients included in the ICM were compared to 132 patients who received standard care. The ICM reduced hospitalizations by 38.2% and ER visits by 69.7%, with reduction of hospitalizations for COPD exacerbation, ER visits and days of hospitalization (p<0.05) compared to standard care. Further, health status improved among the ICM group after 1 year of follow-up (p=0.001), effect sustained over 3 years. However, mortality was not different between groups (p=0.117). Last follow-up CAT score>17 was the strongest independent risk factor for mortality and hospitalization among ICM patients. CONCLUSIONS: An ICM for fe-COPD patients effectively decreases ER and hospital admissions and improves health status, but not mortality.

Implementation of an Integrated Care Model for Frequent-Exacerbator COPD Patients: A Controlled Prospective Study.

INTRODUCTION: Frequent-exacerbator COPD (fe-COPD) associated with frequent hospital admissions have high morbidity, mortality and use of health resources. These patients should be managed in personalized integrated care models (ICM). Accordingly, we aimed to evaluate the long-term effectiveness of a fe-COPD ICM on emergency room (ER) visits, hospital admissions, days of hospitalization, mortality and improvement of health status. METHODS: Prospective-controlled study with analysis of a cohort of fe-COPD patients assigned to ICM and followed-up for maximally 7 years that were compared to a parallel cohort who received standard care. All patients had a confirmed diagnosis of COPD with a history of ≥2 hospital admissions due to exacerbations in the year before enrollment. The change in CAT score and mMRC dyspnea scale, hospital admissions, ER visits, days of hospitalization, and mortality were analyzed. RESULTS: 141 patients included in the ICM were compared to 132 patients who received standard care. The ICM reduced hospitalizations by 38.2% and ER visits by 69.7%, with reduction of hospitalizations for COPD exacerbation, ER visits and days of hospitalization (p<0.05) compared to standard care. Further, health status improved among the ICM group after 1 year of follow-up (p=0.001), effect sustained over 3 years. However, mortality was not different between groups (p=0.117). Last follow-up CAT score>17 was the strongest independent risk factor for mortality and hospitalization among ICM patients. CONCLUSIONS: An ICM for fe-COPD patients effectively decreases ER and hospital admissions and improves health status, but not mortality.

Low erythropoietin plasma levels during exacerbations of COPD.

BACKGROUND: It is known that pro-inflammatory cytokines suppress in vitro the gene expression and protein production of erythropoietin (Epo). We hypothesized that systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) may influence Epo production, particularly during episodes of exacerbation of the disease (ECOPD) where an inflammatory burst is known to occur. OBJECTIVES: We compared the plasma levels of Epo and high-sensitivity (hs) C-reactive protein (hsC-RP) in patients hospitalized because of ECOPD (n = 26; FEV(1): 48 +/- 15% predicted), patients with clinically stable COPD (n = 31; FEV(1): 49 +/- 17% predicted), smokers with normal lung function (n = 9), and healthy never smokers (n = 9). METHODS: Venous blood samples were taken between 9 and 10 a.m. after an overnight fast into tubes with EDTA (10 ml) or without EDTA (10 ml). Plasma levels of Epo (R&D Systems Inc., Minneapolis, Minn., USA) and hsC-RP (BioSource, Belgium) were determined by ELISA. RESULTS: Log-Epo plasma levels were significantly lower (0.46 +/- 0.32 mU/ml) in ECOPD than in stable COPD (1.05 +/- 0.23 mU/ml), smokers (0.95 +/- 0.11 mU/ml) and never smokers with normal lung function (0.92 +/- 0.19 mU/ml) (p < 0.01, each). In a subset of 8 COPD patients who could be studied both during ECOPD and clinical stability, log-Epo increased from 0.49 +/- 0.42 mU/ml during ECOPD to 0.97 +/- 0.19 mU/ml during stability (p < 0.01). In patients with COPD log-Epo was significantly related to hsC-RP (r = -0.55, p < 0.0001) and circulating neutrophils (r = -0.48, p < 0.0001). CONCLUSIONS: These results show that the plasma levels of Epo are reduced during ECOPD likely in relation to a burst of systemic inflammation.

Abnormal levels of circulating endothelial progenitor cells during exacerbations of COPD.

Cardiovascular morbidity and mortality is increased in patients with chronic obstructive pulmonary disease (COPD). Reduced levels of circulating endothelial progenitor cells (EPCs) are associated with increased risk of death in patients with stable coronary artery disease (CAD). Likewise, during acute events of CAD, the number of circulating EPCs increases under the influence of vascular endothelial growth factor (VEGF) and systemic inflammation. Abnormal levels of circulating EPCs have been reported in patients with COPD. However, the response of EPCs to episodes of exacerbation of the disease (ECOPD) has not been investigated yet. We hypothesized that similar to what occurs during acute events of CAD, levels of circulating EPCs would increase during ECOPD. We compared levels of circulating EPCs (assessed by the % of CD34(+)KDR(+) cells determined by flow cytometry) in patients hospitalized because of ECOPD (n = 35; 65 +/- 9 years [mean +/- SD]; FEV(1) = 46 +/- 15% predicted), patients with stable COPD (n = 44; 68 +/- 8 years; FEV(1) = 49 +/- 17% predicted), smokers with normal lung function (n = 10; 60 +/- 9 years), and healthy never smokers (n = 10; 62 +/- 4 years). To investigate potential mechanisms of EPC regulation, we assessed both VEGF and high-sensitivity C-reactive protein (hsC-RP) in plasma. Our results show that EPC levels were higher (p < 0.05) in patients with ECOPD (1.46 +/- 1.63%) than in those with stable disease (0.68 +/- 0.83%), healthy smokers (0.65 +/- 1.11%), and healthy never smokers (1.05 +/- 1.36%). The percentage of circulating EPCs was positively related to VEGF plasma levels during ECOPD (r = 0.51, p = 0.003). In a subset of 12 patients who could be studied during both ECOPD and clinical stability, the EPCs levels increased during ECOPD. We conclude that EPC levels are increased during ECOPD, likely in relation to VEGF upregulation.

[Activity of an intermediate respiratory care unit attached to a respiratory medicine department]. / Actividad de una unidad de cuidados respiratorios intermedios dependiente de un servicio de neumología.

BACKGROUND AND OBJECTIVE: With the development of noninvasive ventilation (NIV), patients with increasingly complex needs have been admitted to respiratory medicine departments. For this reason, such departments in Spain and throughout Europe have been adding specialized respiratory intermediate care units (RICUs) for monitoring and treating patients with severe respiratory diseases. The aim of the present study was to describe the activity of such a RICU. The description may be of use in facilitating the setting up of RICUs in other hospitals of the Spanish National Health Service. METHODS: A systematic record of activity carried out in the RICU of the Hospital Universitario Son Dureta between January and December 2006 was kept prospectively. RESULTS: Of 206 patients with a mean (SD) age of 65 (14) years admitted to the unit, 67% came from the emergency department, 14% from the respiratory medicine department, and 12% from the intensive care unit (ICU). The most common admission diagnoses were exacerbated chronic obstructive pulmonary disease (COPD) (n=97, 47.1%), pneumonia (n=39, 18.9%), heart failure (n=17, 8.2%), and pulmonary vascular diseases (n=18, 8.7%). One hundred twenty-one patients (59%) required NIV. Mean length of stay in the RICU was 5 (5) days. Patients were discharged to the conventional respiratory ward in 79.1% of the cases; 7.8% required subsequent admission to the ICU, and 9.7% died. Of the patients with exacerbated COPD (mean age, 66.5 [10] years; mean length of stay, 4.6 [4.5] days), 67% required NIV, 7.2% required subsequent admission to the ICU, and 8.2% died. CONCLUSIONS: The creation of a RICU by a respiratory medicine department is viable in Spain. Such units make it possible to treat a large number of patients with a low rate of therapeutic failures. Exacerbated COPD was the most common diagnosis on admission to our RICU, and the need for NIV the most common criterion for admission.

[Impact of an on-duty pulmonologist on the activity of a respiratory medicine department]. / Impacto de la presencia de un neumólogo de guardia sobre la actividad de un servicio de neumología.

OBJECTIVE: To evaluate the impact on health care and clinical management of 24-hour coverage by an on-site pulmonologist in a respiratory medicine department. METHODS: In February 2004, a new respiratory medicine 24-hour duty service was started in our hospital. The activity of the on-duty pulmonologist during the following 12 months was systematically and prospectively recorded. The results were put into perspective by comparing the number of monthly admissions and the mean length of stay during the study period with those of the previous 12-month period. RESULTS: During the study period, the on-duty pulmonologist received a mean (SD) of 9.02 (5.27) emergency calls every day, performed 202 diagnostic or therapeutic interventions, and discharged 342 patients. During this period, 1305 patients were admitted to the department (mean length of stay, 8.1 days), whereas in the previous 12 months, with no on-site pulmonologist, 1680 patients were admitted (mean length of stay, 9.0 days). This represents a 22.3% reduction in the annual number of admissions and a reduction in the mean stay by almost 1 day (0.9 days). CONCLUSIONS: The provision of an on-duty pulmonologist was efficient because it facilitated patient turnaround.

Idiopathic Pulmonary Fibrosis: Epidemiology, Natural History, Phenotypes.

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. It is characterized by a chronic, progressive, fibrotic interstitial lung disease of unknown cause that occurs primarily in older adults. Its prevalence and incidence have appeared to be increasing over the last decades. Despite its unknown nature, several genetic and environmental factors have been associated with IPF. Moreover, its natural history is variable, but could change depending on the currently suggested phenotypes: rapidly progressive IPF, familial, combined pulmonary fibrosis and emphysema, pulmonary hypertension, and that associated with connective tissue diseases. Early recognition and accurate staging are likely to improve outcomes and induce a prompt initiation of antifibrotics therapy. Treatment is expected to be more effective in the early stages of the disease, while developments in treatment aim to improve the current median survival of 3⁻4 years after diagnosis.

Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Summary of Recommendations. / Guía de diagnóstico y tratamiento de la hipertensión pulmonar: resumen de recomendaciones.

Pulmonary hypertension is a hemodynamic disorder defined by abnormally high pulmonary artery pressure that can occur in numerous diseases and clinical situations. The causes of pulmonary hypertension are classified into 5 major groups: arterial, due to left heart disease, due to lung disease and/or hypoxemia, chronic thromboembolic, with unclear and/or multifactorial mechanisms. This is a brief summary of the Guidelines on the Diagnostic and Treatment of Pulmonary Hypertension of the Spanish Society of Pulmonology and Thoracic Surgery. These guidelines describe the current recommendations for the diagnosis and treatment of the different pulmonary hypertension groups.

Implementation of an Integrated Care Model for Frequent-Exacerbator COPD Patients: A Controlled Prospective Study / Implementación de un modelo de atención integral para pacientes con EPOC con agudizaciones frecuentes: un estudio prospectivo controlado

Introduction: Frequent-exacerbator COPD (fe-COPD) associated with frequent hospital admissions have high morbidity, mortality and use of health resources. These patients should be managed in personalized integrated care models (ICM). Accordingly, we aimed to evaluate the long-term effectiveness of a fe-COPD ICM on emergency room (ER) visits, hospital admissions, days of hospitalization, mortality and improvement of health status. Methods: Prospective-controlled study with analysis of a cohort of fe-COPD patients assigned to ICM and followed-up for maximally 7 years that were compared to a parallel cohort who received standard care. All patients had a confirmed diagnosis of COPD with a history of ≥2 hospital admissions due to exacerbations in the year before enrollment. The change in CAT score and mMRC dyspnea scale, hospital admissions, ER visits, days of hospitalization, and mortality were analyzed. Results: 141 patients included in the ICM were compared to 132 patients who received standard care. The ICM reduced hospitalizations by 38.2% and ER visits by 69.7%, with reduction of hospitalizations for COPD exacerbation, ER visits and days of hospitalization (p<0.05) compared to standard care. Further, health status improved among the ICM group after 1 year of follow-up (p=0.001), effect sustained over 3 years. However, mortality was not different between groups (p=0.117). Last follow-up CAT score>17 was the strongest independent risk factor for mortality and hospitalization among ICM patients. (AU)

Introducción: La EPOC con agudizaciones frecuentes (EPOC-AF), que se asocia a ingresos hospitalarios recurrentes, presenta altas tasas de morbilidad y mortalidad, y un importante uso de los recursos sanitarios. Estos pacientes deberían ser tratados en modelos de atención integral (MAI) personalizada. Por este motivo, nuestro objetivo fue evaluar la efectividad a largo plazo de un MAI para EPOC-AF valorando las visitas a urgencias, los ingresos hospitalarios, los días de hospitalización, la mortalidad y la mejora del estado de la salud. Métodos: Estudio prospectivo controlado que analizó una cohorte de pacientes con EPOC-AF incluidos en un MAI y en seguimiento durante un máximo de 7 años en comparación con una cohorte paralela que recibió atención estándar. Todos los pacientes tenían diagnóstico confirmado de EPOC y antecedentes de ≥2 ingresos hospitalarios por agudizaciones durante el año anterior a su inclusión en el estudio. Se analizaron los cambios en la puntuación del CAT© y en la escala de disnea del MRC, en los ingresos hospitalarios, las visitas a urgencias, los días de hospitalización y la mortalidad. Resultados: Se compararon 141 pacientes incluidos en el MAI con 132 pacientes que recibieron atención estándar. El MAI redujo las hospitalizaciones en un 38,2% y las visitas a urgencias en un 69,7%, mostrando reducción de las hospitalizaciones por exacerbación de la EPOC, las visitas a urgencias y los días de hospitalización (p<0,05) en comparación con la atención estándar. Además, el estado de salud mejoró en los pacientes del grupo del MAI después de un año de seguimiento (p=0,001), un efecto que se mantuvo durante 3 años. Sin embargo, la mortalidad no fue diferente entre ambos grupos (p=0,117). Una puntuación en el CAT©>17 en el último control de seguimiento fue el factor independiente de riesgo más fuertemente asociado a la mortalidad y la hospitalización de los pacientes en el MAI. (AU)

Noninvasive ventilation during the weaning process in chronically critically ill patients.

Chronically critically ill patients often undergo prolonged mechanical ventilation. The role of noninvasive ventilation (NIV) during weaning of these patients remains unclear. The aim of this study was to determine the value of NIV and whether a parameter can predict the need for NIV in chronically critically ill patients during the weaning process. We conducted a prospective study that included chronically critically ill patients admitted to Spanish respiratory care units. The weaning method used consisted of progressive periods of spontaneous breathing trials. Patients were transferred to NIV when it proved impossible to increase the duration of spontaneous breathing trials beyond 18 h. 231 chronically critically ill patients were included in the study. 198 (85.71%) patients achieved weaning success (mean weaning time 25.45±16.71 days), of whom 40 (21.4%) needed NIV during the weaning process. The variable which predicted the need for NIV was arterial carbon dioxide tension at respiratory care unit admission (OR 1.08 (95% CI 1.01-1.15), p=0.013), with a cut-off point of 45.5 mmHg (sensitivity 0.76, specificity 0.67, positive predictive value 0.76, negative predictive value 0.97). NIV is a useful tool during weaning in chronically critically ill patients. Hypercapnia despite mechanical ventilation at respiratory care unit admission is the main predictor of the need for NIV during weaning.

Airway Mucin 2 Is Decreased in Patients with Severe Chronic Obstructive Pulmonary Disease with Bacterial Colonization.

RATIONALE: Mucins are essential for airway defense against bacteria. We hypothesized that abnormal secreted airway mucin levels would be associated with bacterial colonization in patients with severe chronic obstructive pulmonary disease (COPD) Objectives: To investigate the relationship between mucin levels and the presence of potentially pathogenic micro-organisms in the airways of stable patients with severe COPD Methods: Clinically stable patients with severe COPD were examined prospectively. All patients underwent a computerized tomography scan, lung function tests, induced sputum collection, and bronchoscopy with bronchoalveolar lavage (BAL) and protected specimen brush. Patients with bronchiectasis were excluded. Secreted mucins (MUC2, MUC5AC, and MUC5B) and inflammatory markers were assessed in BAL and sputum by ELISA. MEASUREMENTS AND MAIN RESULTS: We enrolled 45 patients, with mean age (±SD) of 67 (±8) years and mean FEV1 of 41 (±10) % predicted. A total of 31% (n = 14) of patients had potentially pathogenic micro-organisms in quantitative bacterial cultures of samples obtained by protected specimen brush. Patients with COPD with positive cultures had lower levels of MUC2 both in BAL (P = 0.02) and in sputum (P = 0.01). No differences in MUC5B or MUC5AC levels were observed among the groups. Lower MUC2 levels were correlated with lower FEV1 (r = 0.32, P = 0.04) and higher sputum IL-6 (r = -0.40, P = 0.01). CONCLUSIONS: Airway MUC2 levels are decreased in patients with severe COPD colonized by potentially pathogenic micro-organisms. These findings may indicate one of the mechanisms underlying airway colonization in patients with severe COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01976117).

Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs.

Mesenchymal stem cells (MSCs) and macrophages are fundamental components of the stem cell niche and function coordinately to regulate haematopoietic stem cell self-renewal and mobilization. Recent studies indicate that mitophagy and healthy mitochondrial function are critical to the survival of stem cells, but how these processes are regulated in MSCs is unknown. Here we show that MSCs manage intracellular oxidative stress by targeting depolarized mitochondria to the plasma membrane via arrestin domain-containing protein 1-mediated microvesicles. The vesicles are then engulfed and re-utilized via a process involving fusion by macrophages, resulting in enhanced bioenergetics. Furthermore, we show that MSCs simultaneously shed micro RNA-containing exosomes that inhibit macrophage activation by suppressing Toll-like receptor signalling, thereby de-sensitizing macrophages to the ingested mitochondria. Collectively, these studies mechanistically link mitophagy and MSC survival with macrophage function, thereby providing a physiologically relevant context for the innate immunomodulatory activity of MSCs.

Skeletal muscle mitochondrial function is preserved in young patients with chronic renal failure.

Patients with chronic renal failure (CRF) show limited exercise tolerance, classically attributed to anemia. However, persistence of abnormally low peak oxygen consumption, even after restoration of hemoglobin concentration with recombinant erythropoietin therapy and studies of muscle bioenergetics, suggests that the problem is located beyond hemoglobin oxygen transport. The present study is designed to assess mitochondrial respiratory chain (MRC) function from skeletal muscle of patients with CRF to determine whether there is impairment in mitochondrial oxidative capacity. We studied six young patients with CRF on regular hemodialysis and erythropoietin therapy and six healthy controls matched by age, sex, anthropometric characteristics, and physical activity. Muscle biopsy of the quadriceps was performed, and mitochondria were isolated. Mitochondrial content was estimated by means of mitochondrial yield and citrate synthase activity. Maximal capacity for oxygen consumption was measured polarographically using complex I, II, III, and IV substrates of the MRC. Individual enzyme activities of MRC complexes I to V were determined spectrophotometrically. Membrane lipid peroxidation was estimated by cis-parinaric fluorescence. Compared with controls, patients with CRF showed preserved mitochondrial content, conserved respiratory activity, intact enzyme activity of MRC complexes, and no increase in lipid peroxidation. We therefore conclude that mitochondrial function is preserved in young patients with CRF.

Expression of adhesion molecules during apoptosis of circulating neutrophils in COPD.

STUDY OBJECTIVES: Neutrophil accumulation occurs in the lungs of patients with COPD. This can be due to increased recruitment and/or delayed tissue clearance. Previous studies have described alterations in circulating neutrophils in these patients that can facilitate the former. Dysregulation of neutrophil apoptosis may contribute to the latter. This study investigated the potential abnormalities of the apoptotic process in COPD patients. DESIGN: Prospective study. SETTINGS: Outpatient clinic in a urban, tertiary hospital. PATIENTS: Fourteen stable patients with COPD, 8 smokers with normal lung function, and 8 healthy nonsmoking subjects. MEASUREMENTS AND RESULTS: We cultured circulating neutrophils that had been harvested from the study subjects at 2, 6, and 24 h. Apoptosis was assessed using flow cytometry by annexin binding and CD16 expression. The surface expression of the adhesion molecules Mac-1 (CD11b) and L-selectin (CD62L) also was determined by flow cytometry. The percentage of apoptotic neutrophils increased with time similarly in all groups. However, the surface expression of Mac-1 (CD11b) was higher, and that of L-selectin (CD62L) was lower, during apoptosis in the neutrophils of patients with COPD. CONCLUSIONS: These results show that, quantitatively, in vitro neutrophil apoptosis in COPD patients occurred at a rate similar to that found in healthy individuals and smokers with normal lung function. Qualitatively, however, the increased surface expression of Mac-1 (CD11b) and the decreased surface expression of L-selectin (CD62L) observed in the apoptotic neutrophils of COPD patients indicate increased activation during the apoptotic process. This may be relevant for the pathogenesis of COPD.

Clinical value of vasodilator test with inhaled nitric oxide for predicting long-term response to oral vasodilators in pulmonary hypertension.

Acute vasodilator tests with prostacyclin (PGI2) or inhaled nitric oxide (iNO) are used to select patients with pulmonary arterial hypertension (PAH) who should be treated with oral vasodilators. The haemodynamic effects of PGI2 and iNO are different, and the limits for considering a vasodilator response as significant are controversial. The study was aimed to investigate the diagnostic performance of acute vasodilator testing with iNO and PGI2 in predicting the clinical outcome after 1 year treatment with oral vasodilators. Twenty-seven patients with severe PAH were studied. Nineteen patients were treated with oral vasodilators and their outcome after 1 year was qualified as favourable or unfavourable. The diagnostic performance of vasodilator tests in predicting this outcome was evaluated using receiver operating characteristics (ROC) curves. The acute effects of iNO and PGI2 on pulmonary artery pressure (PAP) were similar. By contrast, PGI2 produced more marked changes on cardiac output and pulmonary vascular resistance than iNO (P<0.05). The evolution at 1 year was favourable in 11 patients and unfavourable in 8. Patients with favourable evolution showed greater decrease of PAP with iNO than with PGI2 (P<0.05). The decrease of PAP with iNO had the greatest predictive value on the clinical outcome (area under ROC curve, 0.83). We conclude that in patients with PAH, acute vasodilator testing with iNO is preferable to PGI2 because it reflects more consistently the changes in pulmonary vascular tone. The acute decrease of PAP with iNO is the best predictor of the long-term response to oral vasodilator treatment.