Cytokines in the airway mucosa of subjects with asthma induced by toluene diisocyanate.

To determine the status of activation of lymphocytes and the role of cytokines on the inflammatory response of the bronchial mucosa in toluene diisocyanate (TDI) asthma, we performed a quantitative analysis of bronchial biopsies obtained from 15 subjects with TDI-induced asthma and seven normal control subjects. Markers of activation of lymphocytes (CD25 and Very Late activation Antigen-1, VLA-1) and expression of Tumor Necrosis Factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) were determined by immunohistology in the submucosa. Moreover, expression of adhesion molecules on endothelium of submucosal vessels was assessed. Asthmatic subjects had increased numbers of cells expressing CD25 and VLA-1 compared with the control group (p < 0.05). TNF alpha and IL-1 beta immunoreactivity was increased in asthmatics compared with control subjects (p < 0.01), whereas the expression of adhesion molecules, ICAM-1 and E-selectin, on vascular endothelium was not significantly different. No significant differences in the morphologic quantifications were observed between the asthmatics who had biopsies taken 2 d after TDI challenge (n = 7) and those with longer interval (21 +/- 8 d) between TDI challenge and biopsy (n = 8), suggesting that the increase in CD25, VLA-1, TNF alpha, and IL-1 beta was not due to an acute effect, but could be considered a part of the chronic inflammatory process of the airways. We conclude that the inflammatory response of the airways in TDI-induced asthma is characterized by persistent activation of lymphocytes and by chronic expression of proinflammatory cytokines.

Airway wall remodeling after cessation of exposure to isocyanates in sensitized asthmatic subjects.

To determine whether the cessation of exposure to isocyanates is associated with structural changes of the airway wall in sensitized subjects, we studied bronchial biopsies from 10 subjects with occupational asthma induced by toluene diisocyanate (TDI). Bronchial challenges with TDI and methacholine were performed and biopsies were taken on two occasions, at diagnosis and 6 to 21 mo after cessation of exposure to TDI. After bronchoscopy, biopsies were formalin-fixed or snap-frozen in liquid nitrogen and then processed for a quantitative histochemical and immunohistochemical analysis. After cessation of exposure, we observed a significant decrease of the sensitivity to TDI (p < 0.05), of the thickness of subepithelial fibrosis (p < 0.007), and of the numbers of subepithelial fibroblasts (p < 0.05), mast cells (p < 0.02), and lymphocytes (p < 0.03) as compared with values at diagnosis. By contrast, the nonspecific bronchial hyperresponsiveness and the numbers of macrophages and eosinophils did not change. In conclusion, in patients with occupational asthma induced by TDI, the cessation of exposure to the sensitizing agent is associated with a reduced thickness of subepithelial fibrosis and with a reduced number of subepithelial fibroblasts, mast cells, and lymphocytes in the bronchial mucosa, suggesting a remodeling of the airway wall with the avoidance of the specific stimulus.

Mast cells in the airway mucosa and rapid development of occupational asthma induced by toluene diisocyanate.

We examined lobar bronchial biopsies taken from 18 subjects with occupational asthma induced by toluene diisocyanate (TDI) and from nine nonasthmatic control subjects. Two groups of asthmatics were identified on the basis of the duration of exposure to TDI before the onset of symptoms of asthma. Group A (n = 8) developed asthma after 2.4 +/- 0.4 yr of exposure to TDI, and Group B (n = 10) developed asthma after 21.6 +/- 3.1 yr of exposure to TDI. Both groups of asthmatic subjects had increased numbers of inflammatory cells in the airway mucosa compared with subjects in the nonasthmatic control group. Comparison between Groups A and B showed that subjects who developed asthma after short-term exposure had a significantly increased number of mast cells both in epithelium and in lamina propria than did subjects who developed asthma after long-term exposure to TDI (p < 0.01). Interestingly, the numbers of mast cells both in the epithelium (rs = -0.52, p < 0.05) and in the lamina propria (rs = -0.81, p < 0.001) were inversely correlated with the length of exposure to TDI before the onset of asthma. In conclusion, subjects who develop asthma after short-term exposure to TDI have an increased number of mast cells in the airway mucosa, suggesting that these cells may be associated with individual susceptibility differences to offending agents.

Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate.

We examined the light and electron microscopic structure of lobar bronchial biopsies of nine subjects with occupational asthma induced by toluene diisocyanate (TDI) and of four control nonasthmatic subjects who had never been exposed to TDI. Inflammatory cell numbers were separately assessed in the intact epithelium, in the more superficial layer of the submucosa, and in the total submucosa. Asthmatic subjects had an increased number of inflammatory cells in the airway mucosa compared with control subjects. Eosinophils were significantly increased in all compartments, CD45-positive cells were significantly increased in the epithelium and in the more superficial layer of the submucosa, and mast cells were significantly increased only in epithelium. By electron microscopy eosinophils and mast cells appeared degranulated only in asthmatic patients. In the areas of epithelium that appeared intact by light microscopy, electron microscopy showed that, although the intercellular spaces between columnar cells were similar in asthmatic and control groups, the intercellular spaces between basal cells were significantly wider in patients with asthma. Patients with TDI-induced asthma also had a thicker subepithelial reticular layer, where immunohistochemistry showed the presence of collagen III. In conclusion, in patients with asthma induced by TDI, the airway mucosa shows pathologic features, such as inflammatory cell infiltrate and thickening of subepithelial collagen, similar to those described in atopic asthma.

Effect of cessation of exposure to toluene diisocyanate (TDI) on bronchial mucosa of subjects with TDI-induced asthma.

The effect of cessation of exposure to toluene diisocyanate (TDI) was studied in six patients with TDI-induced asthma, proved by a positive inhalation challenge with TDI. Bronchial challenges with TDI and methacholine were performed, and lobar bronchial biopsies were taken at diagnosis and 6 months later, after cessation of exposure. Biopsies from four nonasthmatic control subjects were also examined. At diagnosis, asthmatic subjects had thickened reticular basement membrane (p less than 0.05) and increased numbers of mononuclear cells (p less than 0.05) and eosinophils (p less than 0.05) in the lamina propria when compared with control subjects. Electron microscopy showed degranulation of eosinophils and mast cells in asthmatics. Six months after cessation of exposure, the thickness of reticular basement membrane was significantly reduced compared with that at diagnosis (p less than 0.05), and it decreased to values similar to those of control biopsies. Inflammatory cell numbers in bronchial mucosa of asthmatic subjects did not change significantly 6 months after removal from exposure, and degranulation of eosinophils and mast cells was still present. At the end of the study, airway hyperresponsiveness to methacholine and/or sensitivity to TDI persisted in most of the asthmatic patients despite the cessation of exposure and the disappearance of asthmatic symptoms. In conclusion, in patients with occupational asthma induced by TDI, the avoidance of exposure to the sensitizing agent for 6 months is able to reverse the reticular basement membrane thickening in the bronchial mucosa, but the inflammatory cell infiltrate, the specific sensitivity to TDI, and the nonspecific airway hyperreactivity may persist.

Leukotriene B4 and late asthmatic reactions induced by toluene diisocyanate.

We investigated whether leukotriene B4 (LTB4) is released from the lungs of sensitized subjects during asthmatic reactions induced by toluene diisocyanate (TDI). We examined three groups of TDI-sensitized subjects, one after no exposure to TDI, the second 8 h after an exposure to TDI that caused an early asthmatic reaction, and the third 8 h after an exposure to TDI that caused a late asthmatic reaction. We analyzed bronchoalveolar lavage (BAL) fluid by reverse-phase high-performance liquid chromatography and by specific radioimmunoassay. The mean concentration of LTB4 was higher [0.31 +/- 0.09 (SE) ng/ml, range 0.15-0.51] in BAL fluid of sensitized subjects who developed a late asthmatic reaction than in BAL fluid of subjects who developed an early asthmatic reaction (0.05 +/- 0.04 ng/ml, range 0-0.224), and no LTB4 was detectable in the control subjects. We also performed BAL 8 h after TDI exposure on four TDI-sensitized late-dual reactors who were on steroid treatment. In this group of subjects no LTB4 was detectable. These results suggest that LTB4 may be involved in late asthmatic reactions induced by TDI.

[Cefotetan in the therapy of respiratory infections. Multicenter research]. / Il cefotetan nella terapia delle infezioni respiratorie. Ricerca multicentrica.

In a controlled multicenter trial 291 patients have been treated with cefotetan. They suffered from acute or chronic exacerbated bronchopulmonary disorders. In 110 patients it was possible to identify the etiological agent: enterobacteria (62), non-fermentative gram-negative bacilli (10), Haemophilus influenzae (8), Branhamella catarrhalis (1), Streptococcus pneumoniae (19), Staphylococcus aureus (12), Streptococcus pyogenes (4). In the exacerbations of chronic bronchitis (203), cefotetan was generally administered at the dose of 1 g/12 h i.m., whereas it was administered at the dose of 2 g/12 h i.v. in acute infection. The mean duration of therapy was 8.8 days. Positive clinical results were obtained in 251 patients (86.2%) with eradication of the pathogen initially isolated in 90.5% of cases. Cefotetan showed good local and general tolerance. The results obtained confirm those of studies concerning limited numbers of patients and show the efficacy of cefotetan both in acute and chronic pathologies, also in patients with serious involvement of their general conditions (concomitant pathologies, high mean age).

[Transtracheal oxygen therapy with oxycath: introduction technic, complications, results in 12 treated patients]. / L'ossigenoterapia transtracheale con oxycath: tecnica di introduzione, complicazioni, risultati in 12 pazienti trattati.

Continuous oxygen therapy is essential in the treatment of advanced chronic obstructive pulmonary disease (COPD). A transtracheal oxygen administration system is more effective in the rehabilitation of these patients than are traditional systems, nasal canula or Venturi mask devices. In the present work the authors describe a simple technique for introducing the transtracheal catheter. The procedure is performed under local anesthesia and a Teflon catheter is inserted between the second and third tracheal rings. In a case study of 12 patients the complications encountered included purulent drainage of the skin tract and accidental displacement of the transtracheal catheter. No procedure related deaths were incurred. Subjectively, the patients experience a sensation of being able to breathe more easily, thus resulting in increased outdoor activity.

Theophylline serum levels unmodified by postprandial administration of a sustained-release preparation (Teonova).

The authors studied serum theophylline levels after administration of new single-dose capsules: Teonova. Special attention was paid to possible fluctuations of serum theophylline after administration of the drug following a standardized meal. For this purpose a test was carried out on eight male patients with intrinsic asthma. The patients were given a dose able to produce a serum concentration of theophylline of between 10 mcg and 20 mcg at the tenth hour after the administration. This dose was found to be 400 mg (2 tablets of 200 mg) for one patient and 600 mg (2 tablets of 300 mg) for the remaining seven. The capsules of Teonova were administered to each patient for two subsequent days at 07h00. On the first day the patients had their capsules after fasting, and on the second day after a standardized meal. The test proved that Teonova assured a satisfactory serum theophylline level throughout the 24 hours in all patients; food in no way affected the absorption kinetics of the drug. Such features make Teonova suitable for long-term theophylline therapy.

Pathogenesis of late asthmatic reactions induced by exposure to isocyanates.

The importance of airways inflammation for the development of bronchial hyperresponsiveness and for exacerbation of asthma was investigated in subjects with occupational asthma. We examined subjects sensitized to isocyanates, a small molecular weight compound that causes occupational asthma. Studies in asthmatic subjects sensitized to toluene diisocyanate (TDI) demonstrated that late, but not early, asthmatic reactions induced by TDI were associated with an acute increase in bronchial responsiveness, and with a marked infiltration of neutrophils and a slight infiltration of eosinophils into the airways, both prevented by steroids. As the late asthmatic reactions and the increase in responsiveness induced by TDI were prevented by steroids, but not by indomethacin, we speculated that cell membrane phospholipid metabolites, which are inhibited by steroids but not by indomethacin, may be involved in TDI induced hyperresponsiveness. The results of these studies suggest that bronchial hyperresponsiveness and exacerbation of asthma may be related to inflammation of the airways and that cell membrane phospholipid metabolites may be involved.

Prednisone inhibits late asthmatic reactions and airway inflammation induced by toluene diisocyanate in sensitized subjects.

To determine the importance of airway inflammation for late asthmatic reactions induced by toluene diisocyanate (TDI), we investigated whether prednisone prevented them [corrected] by modifying the associated airway inflammatory reaction. We measured FEV1 before and at regular intervals after exposure to TDI and performed bronchoalveolar lavage at 8 hours after TDI in two groups of subjects with previously documented late asthmatic reactions, in one group, after no treatment, and in the other group, after treatment with prednisone (50 mg/day for 4 days). After no treatment, each subject developed a late asthmatic reaction, an increase in airway responsiveness, polymorphonuclear leukocytosis, and increased albumin in bronchoalveolar lavage. By contrast, after treatment with prednisone, no subject developed a late asthmatic reaction or an increase in airway responsiveness, and the number of leukocytes and the concentration of albumin were normal in bronchoalveolar lavage. These results suggest that late asthmatic reactions induced by TDI may be caused by airway inflammation and that prednisone may block them [corrected] by inhibiting the inflammatory reaction of the airway induced by TDI in sensitized subjects.

Bronchoalveolar neutrophilia during late asthmatic reactions induced by toluene diisocyanate.

The mechanism by which late asthmatic reactions are induced by toluene diisocyanate (TDI), a low molecular weight chemical that causes occupational asthma in exposed subjects, is unknown. We investigated whether early and late asthmatic reactions induced by TDI are associated with changes in airway responsiveness to methacholine and airway inflammation as determined by bronchoalveolar lavage. We measured FEV1 before and at regular intervals after exposure to TDI, and performed dose-response curves to methacholine and bronchoalveolar lavage at 8 h after TDI in a group of 6 subjects with late asthmatic reactions and in 6 subjects with only early asthmatic reactions. The same procedure was followed 2 h after TDI in a group of 6 subjects with previously documented late asthmatic reactions and in a group of 6 subjects without any previously documented asthmatic reaction after TDI. In subjects with late asthmatic reactions, neutrophils were increased at both 2 and 8 h, and eosinophils and airway responsiveness were increased only at 8 h. By contrast, neutrophils, eosinophils and airway responsiveness were not increased at 8 h after TDI in subjects with an early asthmatic reaction or at 2 h after TDI in normal control subjects. These results suggest that late asthmatic reactions to TDI, and the associated increase in airway responsiveness, may be caused by airway inflammation.

Importance of airway inflammation for late asthmatic reactions induced by toluene diisocyanate in sensitized subjects.

To determine the importance of airway inflammation for late asthmatic reactions and increased airway responsiveness induced by TDI, we investigated whether late asthmatic reactions and increased responsiveness induced by TDI are associated with airway inflammation and whether steroids prevent them by modifying the inflammatory response within the airways. We measured FEV1 before and at regular intervals after exposure to TDI and performed dose-response curves to methacholine and bronchoalveolar lavage 8 hr after TDI in two subjects with previously documented late asthmatic reaction; then we repeated the same procedure a few weeks after treatment with steroids. Airway responsiveness and polymorphonuclear cells were increased in both subjects after the late asthmatic reaction; treatment with steroids prevented late asthmatic reaction and the increase in airway responsiveness and polymorphonuclear cells in bronchoalveolar lavage. These results suggest that late asthmatic reaction induced by TDI may be caused by airway inflammation.

[Typical, atypical and malignant bronchial carcinoid]. / Il carcinoid bronchiale tipico, atipico e maligno.

A series of 54 bronchial carcinoids operated in the course of 12 yr is presented. There were three histological types: typical, atypical and malignant. A parallel was also apparent between histological appearance and clinical pattern. Correct prognosis, however, demands the examination of other parameters, such the tendency of the neoplasia to infiltrate, and the presence of metastatic lymph nodes.