The burden of lung disease in Europe: why a European White Book on lung disease?
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Cost of Illness↗
Biomedical subjects
Y Sibille
Publications and source records attributed to Y Sibille.
[Secretory immunity of the airways].
INTRODUCTION: Continuous exposure of the respiratory tract to inhaled particles and microbes implies the presence of effective defence mechanisms at a bronchial and alveolar level. STATE OF ART: Among the mechanisms involved secretory mucosal immunity contributes considerably to the defence of the bronchial tree. This immunity depends essentially on the active trans-epithelial transport of IgA involved in both innate non-specific and acquired specific immunity. Recently an IgA receptor has been identified on the surface of phagocytes including alveolar macrophages, establishing a link between alveolar and bronchial defences. PERSPECTIVES: The respiratory mucosa represents a crucial interface between the host and its environment, and should provide in the future a new target for the development of diagnostic and therapeutic tools. CONCLUSIONS: Beyond its function as an anatomical barrier the bronchial epithelium possesses a secretory activity that is essential for the protection of the lung. Despite a better understanding of mucosal immunity this secretory activity and in particular the part played by IgA remains to be elucidated.
Antigens, CD↗
Oxidative burst in lipopolysaccharide-activated human alveolar macrophages is inhibited by interleukin-9.
Interleukin (IL)-9 is known to regulate many cell types involved in T-helper type 2 responses classically associated with asthma, including B- and T-lymphocytes, mast cells, eosinophils and epithelial cells. In contrast, target cells mediating the effects of IL-9 in the lower respiratory tract remain to be identified. Therefore, the authors evaluated the activity of IL-9 on human alveolar macrophages (AM) from healthy volunteers. AM preincubated with IL-9 before lipopolysaccharide (LPS) stimulation exhibited a decreased oxidative burst, as previously shown with IL-4. The inhibitory effect of IL-9 was abolished by anti-hIL-9R alpha monoclonal antibody, and presence of IL-9 receptors on AM was demonstrated by immunofluorescence. Both IL-4 and IL-9 failed to modulate tumour necrosis factor-alpha, IL-8 and IL-10 release by LPS-stimulated AM. However, several observations suggested that IL-9 and IL-4 act through different mechanisms: 1) interferon-gamma antagonised the IL4- but not the IL-9-mediated inhibition of AM oxidative burst; 2) expression of CD14 was downregulated by IL-4 but not by IL-9 and 3) production of tumour growth factor-beta by activated AM was potentiated by IL-9 and not by IL4, and was required for the IL-9-mediated inhibition of AM oxidative burst. These observations provide additional information concerning the activity of interleukin-9 in the lung, related to inflammatory or fibrosing lung processes.
Antibodies, Monoclonal↗
Acute exacerbation of chronic obstructive pulmonary disease and antibiotics: what studies are still needed?
The use of antibiotics in acute exacerbations of chronic bronchitis (AECBs) remains the subject of controversy despite considerable medical and socioeconomic implications. First, the contribution of bacterial infection to AECBs is difficult to assess in patients with chronic obstructive pulmonary disease (COPD) who are chronically colonized with respiratory pathogens. In addition, several studies suggest a major role of viral infections in AECBs. Secondly, it is unlikely that all COPD patients will benefit from antibiotics during AECBs. In particular, the benefit in mild COPD remains uncertain. Unfortunately, the number of studies complying with evidence-based medicine requirements is too small for definite recommendations in AECBs to be drawn up. Considering the impact of acute exacerbations of chronic bronchitis on chronic obstructive pulmonary disease patients, as well as the community, and the impact of antibiotic therapy on the development of bacterial resistance, there is an urgent need for the design of appropriate multicentric studies to define the usefulness of this type of treatment in acute exacerbations of chronic bronchitis.
Acute Disease↗
Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease.
The epithelial polymeric immunoglobulin receptor/transmembrane secretory component (pIgR/SC) transports into secretions polymeric immunoglobulin A (pIgA), which is considered the first line of defense of the respiratory tract. The present study, done with quantitative immunohistochemistry, evaluated epithelial expression of secretory component (SC) and Clara cell protein (CC16) and neutrophil infiltration into the airways of eight patients with severe chronic obstructive pulmonary disease (COPD) who were undergoing lung transplantation, as compared with these processes in six nonsmoking patients with pulmonary hypertension who were used as controls and in lung specimens from five smokers without chronic bronchitis. Staining for SC was significantly decreased in the COPD patients as compared with the controls, both in large (mean optical density [MOD]: 23.4 [range: 21.1 to 27.8] versus 42.2 [range: 28.2 to 49.3], p = 0.003) and in small airways (MOD: 30.8 [range: 20.3 to 39.4] versus 41.5 [range: 39.2 to 46.2], p = 0.003). SC expression in small airways correlated strongly with functional parameters such as FEV1 (Kendall's tau (K) = 0.76, p = 0.008), FVC (K = 0.64, p = 0.03), and midexpiratory flow at 50% of VC (MEF50) (K = 0.74, p = 0.01). The reduced expression of SC in large airways correlated with neutrophil infiltration in submucosal glands (K = -0.47, p = 0.03). Expression of CC16 in the bronchial epithelium of COPD patients was also significantly decreased as compared with that of controls, especially in small airways (MOD: 28.3 [range: 26.8 to 32.4] versus 45.8 [range: 40.7 to 56.0], p = 0.002), but no correlation was observed with lung function tests. In conclusion, this study shows that reduced expression of SC in airway epithelium is associated with airflow obstruction and neutrophil infiltration in severe COPD.
Adolescent↗
Lung mucosal immunity: immunoglobulin-A revisited.
Mucosal defence mechanisms are critical in preventing colonization of the respiratory tract by pathogens and penetration of antigens through the epithelial barrier. Recent research has now illustrated the active contribution of the respiratory epithelium to the exclusion of microbes and particles, but also to the control of the inflammatory and immune responses in the airways and in the alveoli. Epithelial cells also mediate the active transport of polymeric immunoglobulin-A from the lamina propria to the airway lumen through the polymeric immunoglobulin receptor. The role of IgA in the defence of mucosal surfaces has now expanded from a limited role of scavenger of exogenous material to a broader protective function with potential applications in immunotherapy. In addition, the recent identification of receptors for IgA on the surface of blood leukocytes and alveolar macrophages provides an additional mechanism of interaction between the cellular and humoral immune systems at the level of the respiratory tract.
Animals↗
Why a series on imaging in the ERJ?
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Diagnostic Imaging↗
Secretory mucosal immune mechanisms.
Mucosal immune mechanisms in the airways are the first specific line of defense, protecting the body from pathogens. The respiratory epithelium actively transports locally produced dimeric IgA in the respiratory secretions by transcytosis, through the pIgR. S-IgA production therefore requires epithelial integrity. S-IgA at the epithelial level is active in several non-inflammatory pathways including intracellular neutralization of virus, antigen excretion, binding to bacterial adhesins. Local IgA production is regulated by various growth factors and cytokines of both epithelial and non-epithelial origin. The respiratory epithelium is thought to play a crucial role in this process. In addition, in chronic airway inflammation, IgA production demonstrates a correlation with eosinophil activation both in vitro and in vivo. While increased IgA and S-IgA production is reported in asthmatics, decreased SC production has been documented in CF and COPD patients, further impairing their local defense mechanisms.
Bronchi↗
Pulmonary effects of short-term exposure to low levels of toluene diisocyanate in asymptomatic subjects.
Isocyanates may be involved in the development of chronic obstructive airway disease among exposed workers. A short-term exposure to toluene diisocyanate (TDI) at concentrations near the permissible levels was investigated to examine whether there was an association with changes in pulmonary function tests and in potential markers of airway injury and inflammation in bronchial lavage (BL) and bronchoalveolar lavage (BAL). Seventeen subjects without respiratory symptoms (eight smokers and nine nonsmokers) were exposed once to ambient air and once to TDI (5 parts per billion (ppb) for 6 h followed by 20 ppb for 20 min) in a randomized, single-blind sequence. Pulmonary function tests were repeatedly assessed during exposure and BAL was performed 1 h after each exposure. Biochemical studies on lavage fluids included albumin, immunoglobulins, antiproteases (alpha2-macroglobulin and alpha1-proteinase inhibitor), potential indicators of epithelial cell function (secretory component and Clara cell protein), and cytokines (tumour necrosis factor-alpha, interleukin (IL)-4, IL-5, IL-6, and IL-8). Exposure to TDI caused a modest decrease in specific airway conductance (sGaw) (p=0.053) and in maximal expiratory flow at 25% of forced vital capacity (MEF25%) (p=0.015) when compared with ambient air. Exposure to TDI resulted in a slight increase in BAL albumin level (TDI: 26.4+/-12.5 versus air: 21.8+/-8.6 microg x mL(-1), p=0.044) and in BL alpha2-macroglobulin concentration (TDI: 0.07+/-0.061 versus air: 0.05+/-0.04 microg x mL(-1), p=0.021). This study suggests that exposure to low toluene disocyanate concentrations is associated with minimal but detectable changes in airway calibre and in epithelial barrier permeability. The pulmonary effects of long-term exposure to low levels of isocyanates require further investigation.
Adult↗
Modulation of intracellular growth of Listeria monocytogenes in human enterocyte Caco-2 cells by interferon-gamma and interleukin-6: role of nitric oxide and cooperation with antibiotics.
The influence of interferon (IFN)-gamma and interleukin (IL)-6 on the intracellular growth of Listeria monocytogenes phagocytosed from the apical pole was examined in polarized Caco-2 cells. IFN-gamma (from the apical pole) and IL-6 (from the basolateral pole) considerably reduced the bacterial intracellular growth, an effect largely abolished by l-monomethyl arginine. Both cytokines caused overexpression of inducible nitric oxide synthase. IL-6, but not IFN-gamma, caused a partial restriction of L. monocytogenes in phagosomes and largely prevented the cytosolic forms from being surrounded by actin. Ampicillin was bacteriostatic in unstimulated cells but modestly bactericidal in cells treated with IFN-gamma and IL-6. Azithromycin (a macrolide) was fairly bactericidal and sparfloxacin (a fluoroquinolone) highly bactericidal in all situations. IFN-gamma and IL-6 may therefore be important determinants in the protection of epithelial cells from intracellular multiplication of L. monocytogenes. Ampicillin may fail in their absence, requiring the use of other antibiotics such as the fluoroquinolones.
Caco-2 Cells↗
Mechanism of the intracellular killing and modulation of antibiotic susceptibility of Listeria monocytogenes in THP-1 macrophages activated by gamma interferon.
Listeria monocytogenes, a facultative intracellular pathogen, readily enters cells and multiplies in the cytosol after escaping from phagosomal vacuoles. Macrophages exposed to gamma interferon, one of the main cellular host defenses against Listeria, become nonpermissive for bacterial growth while containing Listeria in the phagosomes. Using the human myelomonocytic cell line THP-1, we show that the combination of L-monomethyl arginine and catalase restores bacterial growth without affecting the phagosomal containment of Listeria. A previous report (B. Scorneaux, Y. Ouadrhiri, G. Anzalone, and P. M. Tulkens, Antimicrob. Agents Chemother. 40:1225-1230, 1996) showed that intracellular Listeria was almost equally sensitive to ampicillin, azithromycin, and sparfloxacin in control cells but became insensitive to ampicillin and more sensitive to azithromycin and sparfloxacin in gamma interferon-treated cells. We show here that these modulations of antibiotic activity are largely counteracted by L-monomethyl arginine and catalase. In parallel, we show that gamma interferon enhances the cellular accumulation of azithromycin and sparfloxacin, an effect which is not reversed by addition of L-monomethyl arginine and catalase and which therefore cannot account for the increased activity of these antibiotics in gamma interferon-treated cells. We conclude that (i) the control exerted by gamma interferon on intracellular multiplication of Listeria in THP-1 macrophages is dependent on the production of nitric oxide and hydrogen peroxide; (ii) intracellular Listeria may become insensitive to ampicillin in macrophages exposed to gamma interferon because the increase in reactive oxygen and nitrogen intermediates already controls bacterial growth; and (iii) azithromycin and still more sparfloxacin cooperate efficiently with gamma interferon, one of the main cellular host defenses in Listeria infection.
Ampicillin↗
Nosocomial pneumonia: diagnosis, epidemiology and treatment.
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Anti-Bacterial Agents↗
Mechanisms of acute eosinophilic inflammation in a case of acute eosinophilic pneumonia in a 14-year-old girl.
BACKGROUND: Acute eosinophilic pneumonia (AEP) is characterized by respiratory distress, eosinophilic infiltration in the lung, acute onset, resolution of symptoms with corticosteroids and the absence of relapse. Studies to identify the pathophysiology of AEP in adults have demonstrated eosinophil activation in the BAL fluid, and the presence of high levels of interleukin 5 (IL-5) in the BAL. OBJECTIVE: To investigate the pathophysiology of AEP with pleural effusion in a paediatric patient. METHODS: ECP levels in the BALand pleural fluid was determined by radioimmunoassay. IL-5 and GM-CSF concentrations in the BAL and pleural fluid were measured by Elisa. Immunohistochemistry studies performed on open lung biopsy included a specific ICAM-1 immunostaining and a ECP specific immunostaining (EG2+). RESULTS: High levels of ECP were found in the BAL (5 microg/L) and pleural fluid (750 microg/L) demonstrating eosinophil activation at these sites. Immunohistochemistry illustrated activated (EG2+) eosinophils in the interalveolar septa and alveolar space and detected increased expression of ICAM-1 on alveolar epithelial cells. High levels of IL-5 were measured in the BAL (1334 pg/mL) and pleural fluid (7014 pg/mL), while elevated concentrations of GM-CSF (150 pg/mL) were found in the BAL. CONCLUSION: We conclude that in this paediatric patient with AEP activated eosinophils were present in the BAL fluid, in the interalveolar septa and in the pleural space while increased ICAM-1 expression was detected on alveolar epithelial cells, contributing, at least partly, for their adhesive interactions. IL-5 and GM-CSF are likely important to the massive eosinophil recruitment and activation in the lung, while IL-5 is probably related to eosinophil accumulation and activation in the pleural space. Thus, lung generation of eosinophil-active cytokines is central to the pathophysiology of AEP in paediatric patients.
Acute Disease↗
Secretory component production by human bronchial epithelial cells is upregulated by interferon gamma.
Secretory immunoglobulin A (S-IgA) participates in the first noninflammatory line of defence of the respiratory tract. S-IgA consists of dimeric IgA (dIgA) produced by plasma cells and secretory component (SC) produced by epithelial cells. This study compared SC production by primary cultures of human bronchial epithelial cells (HBEC) and by respiratory epithelial cell lines. Among the cell lines, A549 did not produce detectable SC, 16HBE produced very low levels of SC, while CALU-3 produced significant levels of SC. HBEC produced SC in nonpolarized and polarized primary cultures, where it was secreted apically. Polarized HBEC transcytosed radiolabelled and cold dIgA, resulting in the presence of S-IgA in their apical media. SC production and IgA transcytosis by polarized HBEC were upregulated by interferon-gamma (IFN-gamma) after 48 h. By reverse transcription-polymerase chain reaction, no SC messenger ribonucleic acid (mRNA) was detected in A549 and 16HBE, while SC mRNA in CALU-3 was comparable to that of HBEC incubated for 48 h with IFN-gamma. By immunocytochemistry, HBEC expressed SC immunostaining and its intensity increased after 48 h with IFN-gamma. It is concluded that human bronchial epithelial cells produce secretory component and transcytose dimeric immunoglobulin A in vitro. These processes were apically polarized and upregulated by interferon-gamma. Among the cell lines studied, only CALU-3 expressed secretory component-messenger ribonucleic acid and produced detectable secretory component.
Aged↗
Bronchoalveolar lavage: performance, sampling procedure, processing and assessment.
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Asthma↗
Pulmonary perspective: immunology in diagnosis and treatment of lung cancer.
The combination of the limits encountered with current therapies and the increased knowledge of immunology have opened perspectives for the use of immunomodulators in the management of lung cancer patients. Both humoral and cellular immunity are now evaluated in diagnosis and treatment of cancer. Monoclonal antibodies (MoAbs) against tumour-associated antigens are now tested with various imaging techniques to improve detection and staging of lung cancer. MoAbs are also used in therapeutic clinical trials as: 1) mediators of immune effector function; 2) carriers of cytotoxic agents; 3) agents to block tumour growth factor; or 4) anti-idiotype vaccines. Immune effector cells, such as natural killer (NK) cells, T- and B-lymphocytes, macrophages, dendritic cells and neutrophils, are present either within or around tumours and are likely to play a role in cancer. These cells, either alone or with cytokines, could provide new efficient therapeutic approaches, particularly if immunosuppression is involved in tumour progression. In this context, most recent studies using immune cells and molecular bioengineering, could provide additional antitumoral effects. Finally, the discovery of several tumour rejection antigens has revived the dream of designing tumour vaccines and active specific immunotherapy.
Antibodies, Monoclonal↗
Identification of Fc alpha receptor (CD89) isoforms generated by alternative splicing that are differentially expressed between blood monocytes and alveolar macrophages.
One of the hallmarks of mucosal-host defense is the clearance of inhaled Ags by alveolar macrophages (AM) through interactions of IgA Abs and IgA Fc receptors (Fc alpha R). AM constitutively expressed Fc alpha R at lower levels than freshly isolated and in vitro-differentiated monocytes as determined by immunofluorescence using four anti-Fc alpha R mAb. SDS-PAGE analysis of iodinated cell surface proteins revealed that Fc alpha R on AM has an Mr of 50 to 65 kDa, slightly lower than that on monocytes (55-75 kDa). Treatment of AM Fc alpha R by N-glycanase gave rise to a protein core of 28 KDa, smaller than the 32-kDa backbone of blood monocytes. AM Fc alpha R molecules were unaffected by phosphatidylinositol-phospholipase C treatment. Fc alpha R transcripts were analyzed by reverse transcription-PCR using primers in the 5' and 3' regions of a U937 Fc alpha R cDNA. Three transcripts were amplified, cloned, and sequenced from AM and/or monocyte mRNA, the full length Fc alpha R and two alternatively spliced products corresponding to deletions of 66 and 288 nucleotides in the portion coding for the extracellular domain; they were named Fc alpha R a.1, a.2, and a.3, respectively. These PCR products were transcribed and translated in vitro into three proteins (Mr 32, 30, and 22 kDa, respectively), in which the 32- and 30-kDa species were immunoprecipitated by an anti-Fc alpha R mAb. The predicted size of the protein encoded by the Fc alpha R a.2 transcript without the leader peptide is Mr approximately 27,400, a value that is consistent with the Mr of AM Fc alpha R backbone. These results indicate that AM express at their surfaces a protein product of an alternatively spliced Fc alpha R transcript, the Fc alpha R a.2 isoform, that might have physiologic relevance in IgA-mediated host defense at mucosal sites.
Alternative Splicing↗
Occupational asthma due to latex in a hospital administrative employee.
A case is described of occupational asthma caused by indirect exposure to airborne latex allergens in an administrative hospital employee who never used latex gloves.
Adult↗