Mechanisms of respiratory virus-induced asthma exacerbations.
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Acute Disease↗
Biomedical subjects
G Caramori
Publications and source records attributed to G Caramori.
Oxidants in asthma and in chronic obstructive pulmonary disease (COPD).
Experimental and clinical evidences suggest that oxidants play a role in the pathogenesis of respiratory disorders characterised by chronic airway inflammation such as asthma and chronic obstructive pulmonary disease (COPD). The respiratory system is chronically exposed to environmental pollutants, including oxidants. Exogenous sources of oxidants are particularly relevant to the pathogenesis of COPD, being cigarette smoke an extremely rich source of oxidants. In addition, the inflammatory cells recruited to the airways of patients with asthma and COPD, have an exceptional capacity to produce oxidants. Many decades of research have produced a significant amount of data indicating pro-oxidative molecular mechanisms putatively relevant in the pathogenesis of the oxidative stress which characterises these diseases, both locally and systemically. As a consequence, a drug therapy able to restore the redox imbalance in asthma and COPD would probably exert clinical and functional benefits. Indeed, currently available therapies for asthma and COPD can exert an inhibitory effect on oxidant production in the airways. However, it is unknown whether the efficacy of the treatment is somehow linked to the pharmacological modulation of the oxidant/antioxidant balance. So far, it appears that the potential role of antioxidant compounds in the treatment of asthma and COPD has not been fully explored.
Antioxidants↗
Ectopic thymoma simulating a pericardial cyst.
We present a case of a 53 year old man with a thymoma near the pericardium, a rare ectopic localisation of thymoma. A round radiodensity found at the right cardiophrenic angle was initially suspected at the echocardiography to be a pericardial cyst. The diagnosis of thymoma was made only after histopathological examination of the surgically re-sected lesion.
Bronchoscopy↗
Asthma is not a common cause of severe chronic respiratory failure in non-smokers: ALOT study.
BACKGROUND: Little is known about the long-term natural history of asthma and the long-term clinical and functional consequences in non-smoking patients. From a functional point of view, non-smoking asthmatic patients may have a significantly greater decline in forced expiratory volume in one second (FEV1) compared with non-asthmatic subjects and may develop chronic irreversible (fixed) airflow limitation. This has been related to the physiological consequences of chronic airway inflammation causing airway remodeling. However these lesions are all potentially reversible and there is little radiological evidence indicating lung destruction (pulmonary emphysema), which is potentially irreversible, in non-smoking asthmatics. Severe chronic respiratory failure is the major cause of mortality in patients with severe chronic lung diseases. Domiciliary long-term oxygen therapy (LTOT) is an accepted treatment for patients with severe chronic respiratory failure. Our reasoning, therefore, was that if asthma is a cause of severe chronic respiratory failure in non-smokers we should be able to find non-smoking asthmatics within a large population of patients on LTOT. The aim of our study (Asthma and Long-term Oxygen Therapy, "ALOT") was to investigate the prevalence of non-smoking asthmatics in patients on LTOT in a multi-centre, cross-sectional study. METHODS: Between June and September 2003 we screened all subjects on long-term domiciliary oxygen therapy in three different hospitals in the North-East area of Italy (within the provinces of Ferrara and Bologna). Taken collectively, we have found one-hundred and eighty-four patients on LTOT. We have reviewed their clinical data (age, sex, smoking, history and physical examination, arterial blood gas analysis, pulmonary function). RESULTS: 114 patients (all smokers) fulfilled the diagnostic criteria for COPD. Seventy patients (all smokers) had other diseases. We were unable to find any non-smokers in our screened population of subjects on long-term domiciliary oxygen therapy. Furthermore, there was no past history of asthma and/or acute wheezing episodes in either of the patient groups. CONCLUSIONS: This data suggests that asthma is an uncommon cause of severe chronic respiratory failure necessitating long-term domiciliary oxygen therapy in non-smokers and supports the current consensus that asthma and COPD are different diseases with differing stages of severity and the concept that long-term avoidance of active smoking is fundamental for the prevention of severe chronic respiratory failure.
Aged↗
Underuse of spirometry by general practitioners for the diagnosis of COPD in Italy.
BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) underlines that spirometry is the gold standard as the most reproducible, standardised, and objective way of measuring airflow limitation in the diagnosis and assessment of Chronic Obstructive Pulmonary Disease (COPD). However, studies undertaken in different countries have suggested a widespread underuse of spirometry by general practitioners to establish the diagnosis of COPD. Precise estimates of the prevalence of physician-diagnosed COPD in Italy are not currently available. In collaboration with the Italian Academy of General practitioners (SIMG) we have investigated the degree of use of spirometry to establish the diagnosis of COPD in Italy. METHODS: A standardised questionnaire has been self-administered to a sample of 2425 Italian general practitioners (representing 5% of all the Italian doctors involved in general practice). They have been chosen to cover each of the Italian counties. RESULTS: The prevalence of physician-diagnosed COPD was found to be approximately 4%. However, 30% of general practitioners do not use spirometry to establish the diagnosis of COPD. The main reasons given for the failure to use spirometry are (i) that spirometry is not necessary for the diagnosis of COPD or (ii) there are logistical limitations to the access of the patients to lung function laboratories. CONCLUSIONS: This data suggests that contrary to GOLD Guidelines, in Italy, as with other countries, spirometry is not always used in the diagnosis of COPD. There is a clear necessity for further education initiatives targeted to this group of physicians.
Diagnosis, Differential↗
Effect of cigarette smoking on haem-oxygenase expression in alveolar macrophages.
We investigated the effect of chronic cigarette smoking on the expression of haem-oxygenase (HO)-1 and HO-2. Normal subjects and asymptomatic young current smokers with normal lung function tests underwent bronchoalveolar lavage for recovery of macrophages. Reverse transcription/polymerase chain reaction (RT-PCR) analysis showed no significant difference in HO-1 and HO-2 mRNA expression between the two groups. On the other hand, Western blot analysis showed a significant (P<0.05) reduction of HO-2 protein, but not of HO-1, in alveolar macrophages from smokers compared to normal. There was no significant differences by immunocytochemistry for HO-1 and HO-2 expression between the groups. We concluded that HO-2 expression is reduced in alveolar macrophages of smokers, possibly due to the oxidative stress of cigarette smoke. This may in turn lead to reduced protection against further oxidative insults.
Adult↗
Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview.
In the last decade, the analysis of bronchial biopsies and lung parenchyma obtained from chronic obstructive pulmonary disease (COPD) patients compared with those from smokers with normal lung function and non-smokers has provided new insights on the role of the different inflammatory and structural cells, their signalling pathways and mediators, contributing to a better knowledge of the pathogenesis of COPD. This review summarizes and discusses the lung pathology of COPD patients with emphasis on inflammatory cell phenotypes that predominate in different clinical conditions. In bronchial biopsies, a cascade of events takes place during progression from mild-to-severe disease. T lymphocytes, particularly CD8+ cells and macrophages are the prevalent inflammatory cells in the lung of healthy smokers and patients with mild COPD, while total and activated neutrophils predominate in severe COPD. The number of CD4+, CD8+ cells and macrophages expressing nuclear factor-kappa B (NF-kappaB), STAT-4 and IFN-gamma proteins as well as endothelial adhesion molecule-1 in endothelium is increased in mild/moderate disease. In contrast, activated neutrophils (MPO+ cells) and increased nitrotyrosine immunoreactivity develops in severe COPD. In bronchial biopsies obtained during COPD exacerbations, some studies have shown an increased T cell and granulocyte infiltration. Regular treatment with high doses of inhaled glucocorticoids does not significantly change the number of inflammatory cells in bronchial biopsies from patients with moderate COPD. The profile in lung parenchyma is similar to bronchial biopsies. 'Healthy' smokers and mild/moderate diseased patients show increased T lymphocyte infiltration in the peripheral airways. Pulmonary emphysema is associated with a general increase of inflammatory cells in the alveolar septa. The molecular mechanisms driving the lymphocyte and neutrophilic prevalence in mild and severe disease, respectively, needs to be extensively studied. Up-regulation of pro-inflammatory transcription factors NF-kappaB and STAT-4 in mild, activated epithelial and endothelial cells in the more severe disease may contribute to this differential prevalence of infiltrating cells.
Bronchi↗
Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease.
AIMS: To study the expression of mucins in peripheral airways in patients with chronic obstructive pulmonary disease (COPD). METHODS AND RESULTS: Peripheral lung sections from smokers with COPD (n = 9) and age-matched controls including smokers (n = 11) and lifelong non-smokers with normal lung function (n = 6) were stained with alcian blue, periodic acid-Schiff (PAS) and by immunohistochemistry of mucins (MUC): MUC2, MUC4, MUC5AC, MUC5B and MUC6. Histochemical staining and immunoreactivity of bronchiolar epithelium were graded and the presence or absence of stained mucus in the bronchiolar lumen was evaluated. There were no differences in alcian blue and PAS epithelial staining between the three groups. Intraluminal PAS staining was significantly more frequent among COPD subjects (P < 0.05). The expression of MUC5AC was significantly higher in the bronchiolar epithelium of patients with COPD (P < 0.05). Within the bronchiolar lumen, the predominant mucin was MUC5B. Intraluminal MUC5B was significantly more frequent among COPD patients (P < 0.05). CONCLUSIONS: COPD is specifically associated with increased expression of MUC5B in the bronchiolar lumen and of the mucin MUC5AC in the bronchiolar epithelium. These changes in mucin production in the peripheral airways may contribute to the pathophysiology of COPD.
Aged↗
Differential expression of IL-10 receptor by epithelial cells and alveolar macrophages.
BACKGROUND: Interleukin (IL)-10 is a pleiotropic cytokine with a broad spectrum of immunosuppressive and anti-inflammatory effects. IL-10 secretion from alveolar macrophages is defective in patients with asthma and lower concentrations of IL-10 are found in bronchoalveolar lavage (BAL) from asthmatic patients than in normal control subjects. Reduced IL-10 may result in exaggerated and more prolonged inflammatory responses in asthmatic airways. IL-10 acting through the IL-10 receptor (IL-10R) stimulates the transcription factors STAT1 and STAT3. METHODS: We investigated IL-10 and IL-10R expression in normal and asthmatic bronchial epithelium and BAL macrophages using reverse transcription-polymerase chain reaction, immunohistochemistry and Western blotting. The functional effect of IL-10 was examined using granulocyte-macrophage-colony stimulating factor, enzyme-linked immunosorbent assay and Western blotting for phosphorylated STAT1 and STAT3. RESULTS: IL-10 was not expressed in epithelial cells; furthermore these cells did not express the IL-10R and had no functional response to exogenous IL-10. Bronchial epithelial cells expressed variable levels of phosphorylated STAT1 and STAT3 with no change in expression between normal subjects and asthmatics. IL-10 protein and IL-10R expression was detected in alveolar macrophages from all subjects. CONCLUSION: Our study suggests that the bronchial epithelium is not a source of IL-10 and cannot respond to exogenous IL-10 because of a lack of IL-10R expression.
Adult↗
Oxidants and asthma.
Many decades of research have produced a significant amount of data showing increased oxidative stress in asthma and indicating a potential role for oxidants in the pathogenesis of the disease, particularly during exacerbations. Putatively relevant pro-oxidative mechanisms have also been identified. Currently available asthma drugs are generally effective for the treatment of the disease, but their effects on oxidative stress have still not been completely elucidated. From the data available in the literature one can conclude that antioxidant compounds may have a potential role in the treatment of asthma, especially of asthma exacerbations. More convincing evidence from controlled clinical trials is required.
Antioxidants↗
COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma.
BACKGROUND: Squamous cell carcinoma has a stronger association with tobacco smoking than other non-small cell lung cancers (NSCLC). A study was undertaken to determine whether chronic obstructive pulmonary disease (COPD) is a risk factor for the squamous cell carcinoma histological subtype in smokers with surgically resectable NSCLC. METHODS: Using a case-control design, subjects with a surgically confirmed diagnosis of squamous cell carcinoma were enrolled from smokers undergoing lung resection for NSCLC in the District Hospital of Ferrara, Italy. Control subjects were smokers who underwent lung resection for NSCLC in the same hospital and had a surgically confirmed diagnosis of NSCLC of any histological type other than squamous cell. RESULTS: Eighty six cases and 54 controls (mainly adenocarcinoma, n = 50) were enrolled. The presence of COPD was found to increase the risk for the squamous cell histological subtype by more than four times. Conversely, the presence of chronic bronchitis was found to decrease the risk for this histological subtype by more than four times. Among patients with chronic bronchitis (n = 77), those with COPD had a 3.5 times higher risk of having the squamous cell histological subtype. CONCLUSIONS: These data suggest that, among smokers with surgically resectable NSCLC, COPD is a risk factor for the squamous cell histological subtype and chronic bronchitis, particularly when not associated with COPD, is a risk factor for the adenocarcinoma histological subtype.
Aged↗
STAT4 activation in smokers and patients with chronic obstructive pulmonary disease.
Activation of the transcription factor signal transducer and activator of transcription (STAT)-4 is critical for the differentiation of T-helper 1 cells/type-1 cytotoxic T-cells and the production of interferon (IFN)-gamma. Expression of STAT4, phospho-STAT4, IFN-gamma and T-box expressed in T-cells (T-bet) proteins in bronchial biopsies and bronchoalveolar lavage (BAL)-derived lymphocytes, obtained from 12 smokers with mild/moderate chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV1) 59 +/- 16% predicted), 14 smokers with normal lung function (FEV1 106 +/- 12% pred) and 12 nonsmoking subjects (FEV1 111 +/- 14% pred), was examined by immunohistochemistry and immunocytochemistry. In bronchial biopsies of COPD patients, the number of submucosal phospho-STAT4+ cells was increased (240 (22-406) versus 125 (0-492) versus 29 (0-511) cells mm(-2)) when compared with both healthy smokers and control nonsmokers, respectively. In smokers, phospho-STAT4+ cells correlated with the degree of airflow obstruction and the number of IFN-gamma+ cells. Similar results were seen in BAL (2.8 (0.2-5.9) versus 1.03 (0.09-1.6) versus 0.69 (0-2.3) lymphocytes x mL(-1) x 10(3)). In all smokers who underwent lavage, phospho-STAT4+ lymphocytes correlated with airflow obstruction and the number of IFNgamma+ lymphocytes. T-bet expression was not altered in bronchial biopsies and BAL-derived lymphocytes between the three groups. In conclusion, this study suggests that stable mild/moderate chronic obstructive pulmonary disease is associated with an active T-helper 1 cell/type-1 cytotoxic T-cell inflammatory process involving activation of signal transducer and activator of transcription 4 and interferon-gamma production.
Aged↗
Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations.
BACKGROUND: Exacerbations represent an important feature of the clinical manifestation and natural history of chronic obstructive pulmonary disease (COPD). Nuclear localisation of p65 is a signal of nuclear factor-kappaB (NF-kappaB) activation. A study was undertaken to evaluate whether NF-kappaB activation is modified in sputum cells during COPD exacerbations. METHODS: Total and nuclear p65 immunoreactivity was measured by immunocytochemistry in the sputum cells of 11 smokers with moderate COPD during an exacerbation and after 6-8 weeks of clinical stability. RESULTS: Total sputum cell count was significantly increased during exacerbations from a median (IQR) of 880 (510-1865) to 1914.5 (1065-3205) x 10(3)/ml (p<0.05). The main inflammatory cells in the sputum were neutrophils (83.2 (75.4-92.3)%) and macrophages (14.7 (2.6-21.6)%) and their relative proportion did not change during exacerbations. Nuclear staining for p65 was absent in sputum neutrophils, both during exacerbations and in the stable phase. In contrast, the percentage of macrophages expressing nuclear p65 increased significantly during exacerbations from a median (IQR) of 16 (7-24)% to 41.4 (6-69)% (p<0.05). CONCLUSIONS: NF-kappaB appears to be activated in sputum macrophages but not in sputum neutrophils during exacerbations of COPD
Aged↗
Slower rise of exhaled breath temperature in chronic obstructive pulmonary disease.
In chronic obstructive pulmonary disease (COPD) there is decreased vascularity of the bronchi and inflammation of the airways that may have opposite effects on the regulation of heat loss. Exhaled air temperature increase (delta(e) T) was measured in 23 patients with moderate COPD (18 male, mean age +/- SEM 70 +/- 1 yrs; forced expiratory volume in one second (FEV1) 45 +/- 3%, FEV1/forced vital capacity 54 +/- 4%) and 16 normal volunteers (64 +/- 4 yr) and compared to exhaled nitric oxide (eNO) and inflammatory cells in induced sputum as a marker of airway inflammation. Delta(e) T was measured during a flow- and pressure-controlled single exhalation with a fast-response thermometer. delta(e) T was reduced in patients with COPD (1.86 +/- 0.15 delta C x s(-1)) compared to normal subjects (4.00 +/- 0.26 delta C x s(-1)). There was no difference in delta(e) T between patients treated with inhaled steroids and those who were steroid naïve. Delta(e) T was correlated with eNO (r=0.60) but not with sputum neutrophilia. In COPD patients, delta(e) T was increased (2.26 +/- 0.16 delta C x s(-1)) after the inhalation of 200 microg of albuterol, which is a known vasodilator, indicating that delta(e) T and bronchial blood flow may be correlated. Exhaled temperature increase is reduced in chronic obstructive pulmonary disease patients and is increased by the inhalation of vasodilators and therefore may be related to changes of bronchial blood flow and tissue remodelling.
Aged↗
An unusual case of congenital short trachea with very long bronchi mimicking bronchial asthma.
Case reports of a short trachea with early branching of the main bronchi are uncommon. The case is presented of a 64 year old woman with upper airway obstruction due to this anatomical abnormality which caused breathlessness and wheezing that was misdiagnosed (and treated) as bronchial asthma for many years.
Asthma↗
Increased expression of nuclear factor-kappaB in bronchial biopsies from smokers and patients with COPD.
The expression of nuclear factor (NF)-kappaB is an indicator of cellular activation and of inflammatory mediator production. The aim of the present study was to characterise the expression and localisation of p65, the major subunit of NF-kappaB, in the bronchial mucosa of patients with chronic obstructive pulmonary disease (COPD), and to examine the relationship between p65 expression and disease status. Bronchial biopsies were obtained from 14 smokers with COPD, 17 smokers with normal lung function and 12 nonsmokers with normal lung function. The number of p65 positive (+) cells was quantified by immunohistochemistry and the expression of p65 in bronchial biopsies from the three groups was examined by Western blotting (WB). Smokers with normal lung function and patients with COPD had increased numbers of p65+ cells in the epithelium and increased p65 nuclear expression. In COPD patients the number of epithelial p65+ cells correlated with the degree of airflow limitation. WB analysis showed an increase in p65 in smokers with normal lung function and COPD patients (p<0.05). Bronchial biopsies in smokers with normal lung function and chronic obstructive pulmonary disease patients show increased expression of p65 protein, predominantly in the bronchial epithelium. Disease severity is associated with an increased epithelial expression of nuclear factor-kappaB.
Blotting, Western↗
Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma.
Theophylline is well-established in the management of asthma, and there is some evidence of an antiinflammatory effect in asthma. It is not known whether theophylline affects inflammatory markers such as sputum eosinophils and exhaled nitric oxide (NO) in patients with mild asthma not receiving inhaled steroid therapy. In a double-blind, placebo-controlled, cross-over study of 15 patients with mild asthma, we assessed the effect of low-dose theophylline therapy (250 mg twice per day) on eosinophils in induced sputum, bronchoalveolar lavage (BAL) and airway biopsies at the end of both the treatment and placebo periods. Measurements of exhaled nitric oxide (NO) were made at the end of the active and placebo treatment periods of 5 wk each. Low-dose theophylline (mean serum level, 6.1 mg/L) led to a significant reduction in mean (95% confidence interval [CI]) sputum eosinophils from 11.3% (7.80-14.76%) to 8.0% (5.46-10.44%), BAL eosinophils from 3.4% (2.4-4.4%) to 1.7% (1.1-2.3%) and biopsy eosinophils from 1.83% (0.76-2.89%) to 1.20% (0.27-2.13%) compared with placebo (all p < 0.05). There was no significant change in levels of exhaled NO or improvement in lung function and bronchial responsiveness. Low-dose theophylline induced antiinflammatory effects in asthma, reflected by a fall in airway eosinophils with no change in exhaled NO or changes in lung function.
Adult↗
Low-dose theophylline does not exert its anti-inflammatory effects in mild asthma through upregulation of interleukin-10 in alveolar macrophages.
BACKGROUND: There is accumulating evidence that theophylline has anti-inflammatory or immunomodulatory effects. This may be, in part, mediated via an upregulation in the production of the anti-inflammatory cytokine interleukin (IL)-10. We determined whether low-dose theophylline (LDT) would increase the production of IL-10, and attenuate the production of proinflammatory cytokines by alveolar macrophages. METHODS: In a double-blind, placebo-controlled, crossover study involving 15 steroid-free patients with mild asthma, fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed at the end of the treatment and placebo periods. Alveolar macrophages were cultured in vitro, and we measured their release of IL-10, GM-CSF, and TNF-alpha. We also measured IL-10 production in whole blood together with the number of monocytes and T cells expressing intracellular IL-10 by flow cytometry. RESULTS: LDT did not increase the production of IL-10, or attenuate the production of GM-CSF or TNF-alpha by alveolar macrophages. However, after theophylline treatment, there was a significant reduction in mean (SD) (95% CI) BAL eosinophil number from 3.4 (1.7)% (95% CI 2.4-4.4) to 1.7 (1.0)% (95% CI 1.1-2.3) compared with placebo (P<0.05). Similarly, there was no increase in whole-blood IL-10 release or in the number of monocytes and T cells expressing intracellular IL-10 after treatment. CONCLUSIONS: LDT has an anti-inflammatory effect in asthma; however, this effect is not mediated via the production of IL-10 or the attenuation of GM-CSF or TNF-alpha. The mechanisms of theophylline activity remain to be determined.
Adult↗