Oxidative stress-mediated iNKT-cell activation is involved in COPD pathogenesis.

Chronic obstructive pulmonary disease (COPD) is a major clinical challenge mostly due to cigarette smoke (CS) exposure. Invariant natural killer T (iNKT) cells are potent immunoregulatory cells that have a crucial role in inflammation. In the current study, we investigate the role of iNKT cells in COPD pathogenesis. The frequency of activated NKT cells was found to be increased in peripheral blood of COPD patients relative to controls. In mice chronically exposed to CS, activated iNKT cells accumulated in the lungs and strongly contributed to the pathogenesis. The detrimental role of iNKT cells was confirmed in an acute model of oxidative stress, an effect that depended on interleukin (IL)-17. CS extracts directly activated mouse and human dendritic cells (DC) and airway epithelial cells (AECs) to trigger interferonγ and/or IL-17 production by iNKT cells, an effect ablated by the anti-oxidant N-acetylcystein. In mice, this treatment abrogates iNKT-cell accumulation in the lung and abolished the development of COPD. Together, activation of iNKT cells by oxidative stress in DC and AECs participates in the development of experimental COPD, a finding that might be exploited at a therapeutic level.

[Structural abnormalities and inflammation in COPD: a focus on small airways]. / Modifications structurales et inflammation dans la BPCO : importance des voies aériennes distales.

Chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible airflow limitation associated with airway remodelling and inflammation of both large and small airways. The site of airflow obstruction in COPD is located in the small airways, justifying a focus on this compartment. The structural abnormalities that are found in bronchioles with a diameter less than 2mm are characterized by increased airway wall thickness with peribronchial fibrosis, and by luminal obstruction by mucous exudates. Destruction of alveolar walls, the hallmark of emphysema, may be related to protease-antiprotease imbalance, and to mechanisms involving apoptosis, senescence, and autoimmunity. Cigarette smoke inhalation triggers the recruitment of innate immune cells (neutrophils and macrophages) and putatively adaptive immunity mediated via T and B lymphocytes and lymphoid follicles in the small airways. These data suggest a potential role for therapies that can target remodelling and inflammation in the small airways of patients with COPD.

[Exacerbations of asthma in pregnant women]. / Exacerbations de l'asthme chez la femme enceinte.

Prevention of exacerbations and effective treatment is essential in pregnant asthmatic women. The management is well documented. Misunderstanding of the recommendations leads to unsuitable, insufficient treatment and is responsible for more frequent recurrences in the pregnant woman compared with the non pregnant. Above all, good control of the disease and the prevention of exacerbations, based on inhaled corticosteroid therapy and smoking cessation, reduces complications, in particular prematurity and low birth weight.

[Are there specific characteristics of COPD in women?]. / Existe-t-il des spécificités chez les femmes atteintes de BPCO ?

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is a disorder resulting from an interaction between a genetic predisposition, still poorly understood, and the impact of environmental factors including tobacco smoke or professional or domestic air contaminants. BACKGROUND: The prevalence of COPD in the world concerns women as much as men, but it remains under diagnosed among women smokers. The mortality data show an increase in mortality among women compared to men. It thus seems that COPD in women presents more often a particular phenotype, characterized more by bronchial attacks than by emphysema, and by more marked functional effects on the quality of life. Anxiety and depression seem more marked with further repercussions on the quality of life. The effectiveness of treatment may be different, in particular with regard to nicotine weaning and respiratory rehabilitation. VIEWPOINT AND CONCLUSIONS: In the evaluation of chronic diseases in women little is known about COPD. Further studies, focusing specifically on these differences, are needed in order to improve the diagnosis and management of COPD in women.

Clinical COPD phenotypes: a novel approach using principal component and cluster analyses.

Classification of chronic obstructive pulmonary disease (COPD) is usually based on the severity of airflow limitation, which may not reflect phenotypic heterogeneity. Here, we sought to identify COPD phenotypes using multiple clinical variables. COPD subjects recruited in a French multicentre cohort were characterised using a standardised process. Principal component analysis (PCA) was performed using eight variables selected for their relevance to COPD: age, cumulative smoking, forced expiratory volume in 1 s (FEV(1)) (% predicted), body mass index, exacerbations, dyspnoea (modified Medical Research Council scale), health status (St George's Respiratory Questionnaire) and depressive symptoms (hospital anxiety and depression scale). Patient classification was performed using cluster analysis based on PCA-transformed data. 322 COPD subjects were analysed: 77% were male; median (interquartile range) age was 65.0 (58.0-73.0) yrs; FEV(1) was 48.9 (34.1-66.3)% pred; and 21, 135, 107 and 59 subjects were classified in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1, 2, 3 and 4, respectively. PCA showed that three independent components accounted for 61% of variance. PCA-based cluster analysis resulted in the classification of subjects into four clinical phenotypes that could not be identified using GOLD classification. Importantly, subjects with comparable airflow limitation (FEV(1)) belonged to different phenotypes and had marked differences in age, symptoms, comorbidities and predicted mortality. These analyses underscore the need for novel multidimensional COPD classification for improving patient care and quality of clinical trials.

[Asthma: a disease of the whole bronchial tree]. / L'asthme: une maladie de tout l'arbre aérien.

Inflammation and remodelling are constant features of asthma. They are present throughout the whole bronchial tree, even in the small airways (less than 2 mm). The inflammatory cell infiltrate and structural changes are, in most cases, identical. However, in severe asthma, nocturnal asthma and fatal asthma, the cellular infiltrate in the distal airways is more intense and the number of activated cells is increased. In fatal asthma there are major alterations in the distal airways involving the smooth muscle and the bronchial epithelium, and mucus hypersecretion leading to distal airway plugging. Thus the histopathological changes in the distal airways contribute to the most severe stages of asthma and should be targeted by treatment. Currently the non-invasive tools that reflect inflammation are unable to assess these changes in the distal airways.

Airway remodeling is correlated with obstruction in children with severe asthma.

BACKGROUND: Severe asthma may involve an irreversible obstructive pattern, and structural changes in bronchial airways are believed to play a key role in this context. The aim of the present study was to compare airway remodeling in severe asthmatic children with or without obstructive pattern. METHODS: Two groups of children with severe asthma and persistent symptoms, 5-14 years old were included, 15 with persistent obstructive pattern (group O) and 10 without obstructive pattern (group N). Persistent obstructive pattern was defined as a forced expiratory volume in 1 s (FEV(1)) less than 80% of the predicted value after a course of systemic corticosteroids and no significant improvement after bronchodilator. We examined bronchial biopsies by pathological and immunochemical methods and quantified airway smooth muscle (ASM) and mucus gland areas, reticular basement membrane (RBM) thickening, distance between ASM and RBM, muscle light chain kinase (MLCK) expression and number of vessels (CD31 expression). RESULTS: Surface area of ASM (P = 0.009), MLCK expression (P = 0.03) and number of vessels (P = 0.0008) were increased in group O compared with group N. Distance of RBM-ASM was shorter in group O (P = 0.007). FEV(1) negatively correlated with ASM area (r = -0.6; P = 0.002), MLCK expression (r = -0.45; P = 0.02) and CD31 expression (r = -0.7; P = 0.0003), and positively correlated with the distance of RBM-ASM (r = 0.5; P = 0.007). CONCLUSIONS: Structural abnormalities of airway remodeling are present in children with severe asthma. Only an increase in surface area of ASM and the density of the vascular network are more pronounced in children with persistent obstructive pattern, while RBM thickening is similar. These results are concordant with longitudinal studies which emphasize the precocity of bronchial obstruction.

Effects of oxygen on exercise-induced increase of pulmonary arterial pressure in idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a severe disease with no known effective therapy. Patients with IPF may develop severe increase of pulmonary arterial pressure (PAP) on exercise, the mechanisms of which is not clearly identified. OBJECTIVES: To determine whether oxygen may correct the increase of PAP developed during exercise in patients with IPF. PATIENTS AND METHODS: We performed a prospective study on patients with IPF and no hypoxaemia at rest. The absence of pulmonary hypertension (PH) at rest was confirmed by echocardiography (systolic PAP <35 mmHg). Eight patients underwent echocardiography during exercise in air and with oxygen (to maintain saturation of at least 94%). Right ventricle-right atrium gradient and cardiac output were measured at rest, after each increment and at peak. We then compared the echocardiographic results obtained for air and oxygen. RESULTS: All patients developed significant increase of SPAP on exercise (73 +/- 14 mmHg in air). Oxygen did not significantly improve SPAP on exercise (SPAP: 76 +/- 15 mmHg). Echocardiographic characteristics were similar between air and oxygen except for exercise tolerance in term of workload (p=0.045) and endurance (p=0.017). Resting pulmonary function tests did not predict the occurrence of increase of PAP on exercise. CONCLUSION: Our results demonstrate that oxygen does not improve exercise-induced increase of PAP in patients with IPF and support the hypothesis that hypoxic vaso-constriction is not the main mechanism of acute increase of PAP during exercise.

Keratinocyte growth factor improves alterations of lung permeability and bronchial epithelium in allergic rats.

Chronic allergic asthma is associated with marked inflammatory reaction, microvascular leakage and epithelium injury. As previously shown in a rat model of chronic asthma, these alterations increase lung permeability and distal airway fluid clearance. Keratinocyte growth factor (KGF) has been shown to induce epithelial cell proliferation and to protect from acute lung injuries. Therefore, the current authors evaluated the potential role of KGF treatment on lung permeability and airway inflammation in rats with chronic asthma. KGF (1 mg x kg(-1)) was administered intravenously before the last ovalbumin (OVA) challenge in sensitised rats. Permeability was assessed by the leak of radiolabelled albumin from the alveolar and systemic compartments. Histopathological analysis was also performed. Treatment with KGF decreased the leak of both markers and decreased the level of extravascular lung water in sensitised rats challenged with OVA. KGF treatment also reduced the inflammatory cell number in bronchoalveolar lavage fluid but not in bronchial mucosa. KGF markedly limited the allergen-induced alterations in epithelium integrity and the expression of the intercellular junction proteins beta-catenin and zonula occludens protein-1. In conclusion, keratinocyte growth factor administration markedly limits lung permeability and airway inflammation, an effect associated with a decrease in epithelium alterations during chronic allergic asthma. These data open new prospects in the therapeutic strategy of asthma.

[Acute invasive pulmonary aspergillosis in chronic lung disease--a review]. / Aspergillose pulmonaire aiguë invasive et pathologies pulmonaires chroniques.

INTRODUCTION: Apart from malignancies and solid organ transplant, chronic lung disease, in particular chronic obstructive pulmonary disease (COPD), is a third important predisposing factor for acute invasive pulmonary aspergillosis. STATE OF THE ART: COPD is present in 2% of patients dying from invasive aspergillosis. This opportunistic infection occurs because of an immunodeficiency linked both to altered local immunity and to systemic factors such as long term steroid treatment and malnutrition. In patients whose sputum and/or endotracheal aspirate specimens contain hyphal forms of filamentous Aspergillus, half will have a clinically significant aspergillus infection. Diagnostic tests include serum galactomannan antigen test, serum antibody titre, thoracic CT scan and bronchoalveolar lavage (BAL). The identification of fungal hyphae in BAL fluid by microscopy and/or on culture is critical for a positive diagnosis. The mortality rate for acute invasive pulmonary aspergillosis in chronic lung diseases reaches almost 100%. Antifungal monotherapy is still recommended as a first line treatment. Combined treatment can be used in refractory aspergillosis as a salvage therapy. The question of maintaining, decreasing or interrupting steroid treatment must be considered. PERSPECTIVES: Prospective studies are needed to evaluate a standardised diagnostic strategy such as exists for patients with haematological disease. Whether this will improve prognosis remains to be seen. CONCLUSION: Acute invasive pulmonary aspergillosis complicating chronic lung disease is not rare. Improved diagnosis procedures and recent therapeutic advances may have a positive impact on patient prognosis.

[Pulmonary disease in dental laboratory technicians]. / Manifestations pulmonaires des prothésistes dentaires.

INTRODUCTION: The manufacture of dental prostheses exposes the technician to inhalation of various potentially dangerous dusts (silica, hard metals, dental alloys and acrylic resins). BACKGROUND AND VIEWPOINT: Inhalation of dusts produced by the technician in the work place may lead to several respiratory disorders (pneumoconiosis, hypersensitivity pneumonitis, asthma, lung cancer). The continuous development of new materials leads to further manifestations of these disorders and justifies their notification, even in the absence of an accepted occupational disease. This step is taken inconsistently as many dental technicians are not salaried or insured. CONCLUSION: The seriousness of some of these disorders and the absence of effective treatment makes it important to develop effective methods of prevention for the protection of individuals and groups, and for early detection.

Necrotising sarcoid granulomatosis: clinical, functional, endoscopical and radiographical evaluations.

Necrotising sarcoid granulomatosis (NSG) is a rare disease diagnosed on the basis of pathological features. The present study reports the characteristics of 14 cases of NSG. The mean age at the appearance of first symptoms was 37 yrs and the mean delay between first symptoms and diagnosis was 1 yr. Extrarespiratory symptoms were more common (12 out of 14) than respiratory symptoms (eight out of 14). Seven patients had inflammatory syndrome. Bronchoalveolar lavage was performed in eight patients and found to be normal in three cases. Respiratory function was normal in 13 patients, but carbon monoxide diffusing capacity was slightly decreased in eight of the 11 patients tested. A computed tomography scan showed a solitary nodule in four out of 14 cases, bilateral nodules in three and infiltrates in seven. One patient died from neurological complications despite treatment with corticosteroids and immunosuppressive drugs. Two cases of relapse were observed in patients initially treated with corticosteroids, and there were two cases of relapse after surgery. No relapse occurred in the five untreated patients. During the follow-up, lung cancer was detected at 26 months and 8 yrs, respectively, after NSG diagnosis in two patients. In conclusion, no one treatment is associated with a better outcome than the others, although lung biopsy might be necessary in case of isolated nodule or cavitation. Greater vigilance is required during the follow-up.

Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.

The syndrome resulting from combined pulmonary fibrosis and emphysema has not been comprehensively described. The current authors conducted a retrospective study of 61 patients with both emphysema of the upper zones and diffuse parenchymal lung disease with fibrosis of the lower zones of the lungs on chest computed tomography. Patients (all smokers) included 60 males and one female, with a mean age of 65 yrs. Dyspnoea on exertion was present in all patients. Basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests were as follows (mean+/-sd): total lung capacity 88%+/-17, forced vital capacity (FVC) 88%+/-18, forced expiratory volume in one second (FEV1) 80%+/-21 (% predicted), FEV1/FVC 69%+/-13, carbon monoxide diffusion capacity of the lung 37%+/-16 (% predicted), carbon monoxide transfer coefficient 46%+/-19. Pulmonary hypertension was present in 47% of patients at diagnosis, and 55% during follow-up. Patients were followed for a mean of 2.1+/-2.8 yrs from diagnosis. Survival was 87.5% at 2 yrs and 54.6% at 5 yrs, with a median of 6.1 yrs. The presence of pulmonary hypertension at diagnosis was a critical determinant of prognosis. The authors hereby individualise the computer tomography-defined syndrome of combined pulmonary fibrosis and emphysema characterised by subnormal spirometry, severe impairment of gas exchange, high prevalence of pulmonary hypertension, and poor survival.

Allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) occurs in nonimmunocompromised patients and belongs to the hypersensitivity disorders induced by Aspergillus. Genetic factors and activation of bronchial epithelial cells in asthma or cystic fibrosis are responsible for the development of a CD(4)+Th2 lymphocyte activation and IgE, IgG and IgA-AF antibodies production. The diagnosis of ABPA is based on the presence of a combination of clinical, biological and radiological criteria. The severity of the disease is related to corticosteroid-dependant asthma or/and diffuse bronchiectasis with fibrosis. The treatment is based on oral corticosteroids for 6-8 weeks at acute phase or exacerbation and itraconazole is now recommended and validated at a dose of 200 mg/day for a duration of 16 weeks.

[Endocrine and pulmonary histiocytosis: a case diagnosed through stereotoxic biopsy]. / Histiocytose X pulmonaire et hypothalamo-hypophysaire, diagnostiquée par biopsie cérébrale stéréotaxique.

INTRODUCTION: Despite intensive investigation, the pulmonary lesions of Langerhans cell histiocytosis can sometimes prove difficult to yield a diagnosis of this potentially multi-focal disease. CASE REPORT: We report the case of a sixteen year old woman, who presented with a hypothalamo-hypophyseal mass associated with endocrine clinical signs, dyspnoea, and micro-nodular pulmonary lesions on computerised tomography. A Langerhans cell histiocytosis was initially suspected, but then thought unlikely in the light of negative pulmonary investigations and spontaneous regression of the pulmonary lesions. However, an increase in the size of the cerebral mass prompted a brain biopsy finally confirming the diagnosis of Langerhans cell histiocytosis. CONCLUSIONS: This case report identifies a possible dissociation between the clinical courses of cerebral and pulmonary Langerhans cell histiocytosis, and confirms the usefulness of extra-thoracic biopsies in making a diagnosis on the disseminated form of the disease.