Piera Boschetto

Plasma exudation. Correlation between Evans blue dye and radiolabeled albumin in guinea pig airways in vivo

We quantified the tissue exudation and luminal transudation of two plasma markers, Evans blue (EB) dye and [125I]-human serum albumin (HSA), into the airways of the anesthetized guinea pig in response to platelet activating factor (PAF). There was a highly significant correlation between the tissue content of EB and [125I]-HSA in all airways studied. Significant correlation for transudation of the two markers was limited to high rates of plasma leakage. [125I]-HSA was the more sensitive marker for the association between exudation and transudation and the effect of PAF on transudation. EB was the better marker for assessing the relationship between the dose of PAF and plasma exudation.

Association between markers of emphysema and more severe chronic obstructive pulmonary disease

Background: The predominant emphysema phenotype is associated with more severe airflow limitation in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate whether COPD patients, with or without emphysema quantitatively confirmed by high resolution computed tomography (HRCT), have different COPD severity as assessed by the BODE index (body mass index, airflow obstruction, dyspnoea, exercise performance) and inspiratory capacity to total lung capacity ratio (IC/TLC), and by different biological markers of lung parenchymal destruction. Methods: Twenty six outpatients with COPD and eight healthy non-smokers were examined. Each subject underwent HRCT scanning, pulmonary function tests, cell counts, and measurements of neutrophil elastase, matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in induced sputum, as well as measurement of desmosine, a marker of elastin degradation in urine, plasma and sputum. Results: Patients with HRCT confirmed emphysema had a higher BODE index and lower IC/TLC ratio than subjects without HRCT confirmed emphysema and controls. Forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity ratio, and carbon monoxide transfer coefficient were lower, whereas the number of eosinophils, MMP-9, and the MMP-9/TIMP-1 ratio in sputum were higher in patients with emphysema. In COPD patients the number of sputum eosinophils was the biological variable that correlated positively with the HRCT score of emphysema (p = 0.04). Conclusions: These results suggest that COPD associated with HRCT confirmed emphysema is characterised by more severe lung function impairment, more intense airway inflammation and, possibly, more serious systemic dysfunction than COPD not associated with HRCT confirmed emphysema.

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.

Mechanisms and pathology of occupational asthma

Since the pathogenesis and the pathological features of occupational asthma are similar to those of nonoccupational asthma, the former represents a very useful model for the investigation of the pathogenesis of asthma in general. More than one mechanism may be operative in occupational asthma. Among the mechanisms proposed, immunological mechanisms and airway inflammation play an important role. There is evidence to confirm that T-lymphocyte activation and local accumulation in the bronchial wall of activated eosinophils occurs in asthma of diverse aetiology, i.e. immunoglobulin E (IgE)-mediated, occupational and intrinsic. Neurogenic pathways should be further investigated as a potential mechanism of modulation and amplification of airway inflammation in occupational asthma.

Chronic obstructive pulmonary disease (COPD) and occupational exposures

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in both industrialized and developing countries.Cigarette smoking is the major risk factor for COPD. However, relevant information from the literature published within the last years, either on general population samples or on workplaces, indicate that about 15% of all cases of COPD is work-related.Specific settings and agents are quoted which have been indicated or confirmed as linked to COPD. Coal miners, hard-rock miners, tunnel workers, concrete-manufacturing workers, nonmining industrial workers have been shown to be at highest risk for developing COPD.Further evidence that occupational agents are capable of inducing COPD comes from experimental studies, particularly in animal models.In conclusion, occupational exposure to dusts, chemicals, gases should be considered an established, or supported by good evidence, risk factor for developing COPD. The implications of this substantial occupational contribution to COPD must be considered in research planning, in public policy decision-making, and in clinical practice.

Predominant emphysema phenotype in chronic obstructive pulmonary disease patients

Patients with fixed airflow limitation are grouped under the heading of chronic obstructive pulmonary disease (COPD). The authors investigated whether COPD patients have distinct functional, radiological and sputum cells characteristics depending on the presence or absence of emphysema. Twenty-four COPD outpatients, 12 with and 12 without emphysema on high-resolution computed tomography scan of the chest, were examined. Patients underwent chest radiography, pulmonary function tests and sputum induction and analysis. Subjects with documented emphysema had lower forced expiratory volume in one second (FEV1), FEV1/forced vital capacity ratio, and lower carbon monoxide diffusion constant (KCO), compared with subjects without emphysema. Chest radiograph score of emphysema was higher, chest radiograph score of chronic bronchitis was lower, and the number of sputum lymphocytes was increased in patients with emphysema, who also showed a negative correlation between KCO and pack-yrs. Chronic obstructive pulmonary disease patients with emphysema, documented by high-resolution computed tomography scan, have a different disease phenotype compared with patients without emphysema. Identification of chronic obstructive pulmonary disease-related phenotypes may improve understanding of the natural history and treatment of the disease.

Long-term follow-up of toluene diisocyanate-induced asthma

Eighty-seven cases of occupational asthma induced by toluene diisocyanate (TDI) were diagnosed by an inhalation challenge with TDI and methacholine. After an average follow-up interval of 11 yrs, all subjects were re-examined. Of the 87 subjects examined, 13 (15%) had remained in the same job, 44 (50.5%) had been removed from exposure for <10 yrs and 30 (34.5%) had been removed for >10 yrs. The proportion of subjects who experienced symptoms of asthma and those who were hyperresponsive to methacholine was significantly lower. Of the patients, 59% used short-acting bronchodilators, 8% long-acting bronchodilators and 18% were on regular inhaled glucocorticoids. Thus, multiple regression analysis showed a positive correlation between forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) at follow-up and FVC and FEV1 at diagnosis, and a negative correlation with smoking and with therapy with bronchodilators. Stepwise logistic regression showed that the follow-up provocative dose causing a 20% fall in the FEV1 (PD20) could be predicted from baseline PD20. These results indicate that respiratory symptoms and airway hyperresponsiveness to methacholine persist in subjects removed from exposure to TDI for >10 yrs. A more favourable prognosis was associated with a better lung function and a lower degree of airway hyperresponsiveness to methacholine at diagnosis.

Interleukin‐13 and ‐4 expression in the central airways of smokers with chronic bronchitis

The aim of this study was to determine whether the T‐helper 2‐type cytokines interleukin (IL)‐13 and ‐4 are involved in mucus hypersecretion, the hallmark of chronic bronchitis (CB). Surgical specimens were examined from 33 subjects undergoing lung resection for localised peripheral malignant pulmonary lesions: 21 smokers with symptoms of CB, 10 asymptomatic smokers (AS) and two nonsmokers with normal lung function. The number of IL‐4 and ‐13 positive (+) cells in the central airways was quantified. To better assess the cytokine profile, a count was also made of IL‐5+ and interferon (IFN)‐γ+ cells. Compared to AS, the CB group had an increased number of IL‐13+ and ‐4+ cells in the bronchial submucosa, while the number of IL‐5+ and IFN‐γ+ cells were similar in all the groups. No significant associations were found between the number of cells expressing IL‐13 or ‐4 and the number of inflammatory cells. Double labelling showed that 13.2 and 12.9% of IL‐13+ cells were also CD8+ and CD4+, whereas 7.5 and 5% of IL‐4+ cells were CD8+ and CD4+, respectively. In conclusion, T‐helper‐2 and ‐1 protein expression is present in the central airways of smokers and interleukin‐4 and ‐13 could contribute to mucus hypersecretion in chronic bronchitis.

Expression of protease activated receptor-2 (PAR-2) in central airways of smokers and non-smokers.

Background: Protease activated receptor-2 (PAR-2) is a transmembrane G protein coupled receptor preferentially activated by trypsin and tryptase. The protease activated receptors play an important role in most components of injury responses including cell proliferation, migration, matrix remodelling, and inflammation. Cigarette smoking causes an inflammatory process in the central airways, peripheral airways, lung parenchyma, and adventitia of pulmonary arteries. Methods: To quantify the expression of PAR-2 in the central airways of smokers and non-smokers, surgical specimens obtained from 30 subjects undergoing lung resection for localised pulmonary lesions (24 with a history of cigarette smoking and six non-smoking control subjects) were examined. Central airways were immunostained with an antiserum specific for PAR-2 and PAR-2 expression was quantified using light microscopy and image analysis. Results: PAR-2 expression was found in bronchial smooth muscle, epithelium, glands, and in the endothelium and smooth muscle of bronchial vessels. PAR-2 expression was similar in the central airways of smokers and non-smokers. When smokers were divided according to the presence of symptoms of chronic bronchitis and chronic airflow limitation, PAR-2 expression was increased in smooth muscle (median 3.8 (interquartile range 2.9–5.8) and 1.4 (1.07–3.4) respectively); glands (33.3 (18.2–43.8) and 16.2 (11.5–22.2), respectively); and bronchial vessels (54.2 (48.7–56.8) and 40.0 (36–40.4), respectively) of smokers with symptoms of chronic bronchitis with normal lung function compared with smokers with chronic airflow limitation (COPD), but the increase was statistically significant (p<0.005) only for bronchial vessels. Conclusions: PAR-2 is present in bronchial smooth muscle, glands, and bronchial vessels of both smokers and non-smokers. An increased expression of PAR-2 was found in bronchial vessels of patients with bronchitis compared with those with COPD.

Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer.

Interleukin (IL)-10 is expressed in many solid tumours and plays an ambiguous role in controlling cancer growth and metastasis. In order to determine whether IL-10 is involved in tumour progression and prognosis in nonsmall cell lung cancer (NSCLC), IL-10 expression in tumour cells and tumour-associated macrophages (TAMs) and its associations, if any, with clinicopathological features were investigated. Paraffin-embedded sections of surgical specimens obtained from 50 patients who had undergone surgery for NSCLC were immunostained with an antibody directed against IL-10. TAMs and tumour cells positive for IL-10 were subsequently quantified. IL-10-positive TAM percentage was higher in patients with stage II, III and IV NSCLC, and in those with lymph node metastases compared with patients with stage I NSCLC. High IL-10 expression by TAMs was a significant independent predictor of advanced tumour stage, and thus was associated with worse overall survival. Conversely, IL-10 expression by tumour cells did not differ between stages II, III and IV and stage I NSCLC. In conclusion, interleukin-10 expression by tumour-associated macrophages, but not by tumour cells, may play a role in the progression and prognosis of nonsmall cell lung cancer. These results may be useful in the development of novel approaches for anticancer treatments.