Bronchial biopsy findings in intermittent or "early" asthma.

Bronchial biopsy specimens from subjects with intermittent or "early" asthma were compared with specimens taken from healthy subjects. Patients with early asthma included those with seasonal asthma and occupational asthma. There was a small but statistically significant increase in the thickness of the subepithelial extracellular matrix protein tenascin in subjects with seasonal and occupational asthma compared with control subjects. Collagen types IV and VII were increased only in patients with occupational asthma. Eosinophils were the only inflammatory cells that were significantly increased in subjects with seasonal asthma compared with control subjects. These data show that inflammation is present in the airways of patients with early asthma, and the increase in tenascin expression in the basement membrane zone suggests that structural changes are also initiated at an early stage of the disease.

Expression of laminins in the airways in various types of asthmatic patients: a morphometric study.

Laminins (Ln) are crucial in airway morphogenesis. Because they are able to interact with inflammatory cells, they are likely to participate in inflammation accompanied by airway structural remodeling in asthma. Taking biopsies and using immunohistochemistry and quantitative image analysis, we characterized the distribution of Ln chains alpha 1, alpha 2, and beta 2 in the bronchial mucosa of patients with seasonal (n = 17), early occupational (n = 8), and chronic asthma (n = 16) for comparison with that of normal controls (n = 8). In all asthmatic patients, both Ln chains alpha 1 and beta 2 were confined to the superficial margin of the basement membrane (BM), blood vessels, and smooth muscle. The thickness of Ln beta 2 expression in BM was significantly greater in patients with chronic (1.9 +/- 0.1 microns; P < 0.001) and occupational asthma (1.7 +/- 0.1 microns; P < 0.05) than in controls (0.4 +/- 0.3 microns). Only in patients with occupational asthma was the thickness of the Ln alpha 1 layer (2.3 +/- 0.2 microns; mean +/- SEM) significantly different from that in controls (1.4 +/- 0.5 microns; P < 0.05). There was no immunoreactivity for the Ln alpha 2 chain in controls or patients with mild asthma, but in clinically severe chronic asthma we found a discontinuous staining along the epithelial margin of the BM. Since Ln chains alpha 2 and beta 2 appear to function only during morphogenesis, increased expression of these Ln chains in adult asthma patients suggests accelerated tissue turnover in the airways, possibly as a result of airway inflammation in asthma.

Capsaicin-induced cough in humans.

We have evaluated the properties of capsaicin as a selective cough-inducing agent in healthy human subjects. Despite frequent coughing, the subjects could inhale repeated breaths of capsaicin aerosol during 60 s without difficulty. Cough started immediately on inhalation and was most intense during the first 30 s. Cough always disappeared promptly when the capsaicin inhalation was terminated. The cough response was well reproducible and concentration-dependent up to 10 microM; at higher concentrations there was a distinct plateau of the cough response. Specific airway conductance was not changed 3 min after 50 microM capsaicin. Capsaicin (> or = 10 microM) had a burning taste, but there were no visual signs of pharyngitis or laryngitis. Citric acid (nebulized solutions 0.125 to 32%) had a choking effect and could be administered only as single breaths. There was no correlation between the cough response to citric acid and to capsaicin. Inhaled lidocaine (20 and 80 mg from nebulized solutions) caused a dose-dependent inhibition of capsaicin-induced cough. Lidocaine suppressed citric acid-induced cough as effectively as capsaicin-induced cough. In conclusion, we have characterized capsaicin-induced cough and demonstrated that it can be a useful tool in the study of cough reactivity and for evaluation of antitussive agents in humans. Capsaicin may be complementary to citric acid and may offer experimental advantages over this traditional tussive stimulus.

Acute and long-term airway hyperreactivity in aluminium-salt exposed workers with nocturnal asthma.

Nineteen young male workers exposed occupationally from 1975-1977 to inhaled particles of aluminium fluoride or sulphate at 2 plants, developed nocturnal wheezing and breathlessness with reversible airways obstruction after an average of 4 months employment. At standardized methacholine provocation tests (MPT), 17 of 19 workers with normal spirometry showed airway hyperreactivity with a fall of FEV1 of greater than or equal to 15% after 0.1% methacholine. We followed 15 initially asthmatic workers for 2-5 years with MPT. Mean TD 15% FEV1 in 11 workers did not change significantly after an average of 41 months of non-exposure. Six workers continuously exposed for 48 months also failed to change their TD 15% FEV1 MCh. In 1983, only one subject had returned to normal airway reactivity. We have no reason to suspect inducing agents other than aluminium salts.

Bronchial reactivity in patients with recent pulmonary sarcoidosis.

Non-specific bronchial reactivity was assessed in 17 consecutive non-smoking and non-steroid treated patients with recently diagnosed pulmonary sarcoidosis, 11 with stage I disease and six with stage II disease. Bronchial reactivity was measured by recording the FEV1 after increasing doses of methacholine. Three subjects with asthma were hyperreactive. The 14 subjects with no asthma had a mean FEV1 of 96% predicted. Only one was hyperreactive, with a fall in FEV1 of over 15% after 0.1% methacholine. The median provocative concentration causing a 15% fall in FEV1 did not differ from that in a normal population studied previously. It is concluded that sarcoidosis seldom induces airway hyperreactivity within one year of diagnosis in patients with normal spirometric values.

Bronchial reactivity and small airway dysfunction in subjects with intermediate alpha 1-antitrypsin deficiency.

Lesions in small airways may cause increased central deposition of inhaled aerosol. This may enhance airway constriction following methacholine (MCh) challenge. Heterozygous alpha 1-antitrypsin deficiency (PiMZ) and smoking may both act on the lung parenchyma and may also influence small airways. We, therefore, have related bronchial reactivity to MCh to the function of the small airways and to smoking habits in 31 normal (PiM) male subjects aged 48-50 years and 34 PiMZ male subjects, all from a population study. A total of 23 subjects with increased bronchial reactivity was found. The number of reacting smokers (14/23) was significantly higher than that of the reacting ex-smokers (7/23) (p less than 0.05) and nonsmokers (2/19) (p less than 0.05). The smokers who had increased reactivity to MCh challenge had significantly higher closing capacity %, RV/TLC %, and volume of trapped gas % than the smokers who did not have increased reactivity. This difference was not seen with regard to closing volume %, slope index, delta N2 %/1, or washout volume. There was no significant difference between the PiM and the PiMZ subjects with regard to any of the lung function variables or the response to the MCh challenge. It is concluded that there may be a correlation between dysfunction of the small airways and increased bronchial reactivity.

Non-specific bronchial hyperreactivity: correlation to asthma and modifying factors.

Bronchial hyperreactivity can be induced and modified by allergic and non-allergic factors affecting the airways. Bronchospasm can also be induced by small amounts of many of these agents and by other factors as well. Allergic and non-allergic subjects can be affected. Bronchial obstruction in asthma due to allergic reactions is to a large extent dependent on the degree of nonspecific bronchial reactivity. This can be influenced by different modes of treatment.

Aryl hydrocarbon hydroxylase induction levels in patients with malignant tumors associated with smoking.

The levels of aryl hydrocarbon hydroxylase (AHH) inducibility were assessed in 173 patients with cancers statistically associated with smoking, i.e., squamous cell and transitional cell carcinomas, at various sites. In 34 patients with carcinomas of the oral cavity, 41 patients with laryngeal carcinomas, and 22 patients with pulmonary carcinomas there was a highly significant overrepresentation of high inducers, whereas 30 patients with carcinomas of the renal pelvis and ureter and 46 patients with urinary bladder carcinomas did not differ significantly in this respect from a control population comprising 92 subjects with no history of neoplastic disease. The results add further support to the concept of AHH as a major activator of carcinogens belonging to the group of polycyclic aromatic hydrocarbons (PAH) when these affect the oral cavity and/or the respiratory tract. The role of AHH in urothelial carcinogenesis seems to be less explicit.

Propagation of a poorly differentiated human pulmonary adenocarcinoma in nude athymic rats.

Nude athymic rats of Rowett genetic background were injected subcutaneously with cells from a poorly differentiated human pulmonary adenocarcinoma, following propagation in nude mice. The tumour cells were obtained by thoracentesis and by pleural biopsy during thoracoscopy. So far, we have heterotransplanted 13 different malignant human tumours including malignant mesothelioma, pulmonary adenocarcinoma, malignant melanoma and malignant lymphoma. Subcutaneous tumour growth was seen in all inoculated animals, with an exponential tumour growth pattern and with tumour volume doubling times of approximately 8 days. After two initial passages in nude athymic mice of BALB/c genetic background, the human tumour so far has undergone 9 passages in athymic rats, i.e. collection of tumour material by biopsy from the preceding tumour-bearing rat generation, processing and inoculation of tumour brei with subsequent tumour growth have been repeated 8 times. Four-to-8-week-old rats of both sexes were used throughout and tumour growth was controlled by palpation twice a week. Routine histopathological sections were prepared from the tumour at various passages to assess similarity to the original tumour in the patient. The growth pattern of the xenografts remained similar at all passages just as the remarkable similarity of the heterotransplanted tumours to the original adenocarcinoma was retained at all passages. No spontaneous regressions of heterotransplanted tumours could be demonstrated. Electron microscopical analysis revealed numerous blunt microvilli and lumina partly filled with conglomerates of mucigen granules and small glycocalyceal bodies associated with external superficial microvilli. Scantiness of dark secretory granules together with free and membrane-bound polyribosomes were seen in the cytoplasm. We believe that the nude athymic rat is a valuable research tool and that the permanently transplantable human tumour reported here could be of value in delineating further the mechanisms for tumour take, growth and control.

Does atropine block antigen-induced contraction in canine bronchial rings? A preliminary report.

Isometric contractions recorded with a strain gauge, were elicited with cumulative doses of ascaris suum antigen on fresh canine bronchial rings from 8 dogs. Fifteen rings from 2 spontaneously sensitized dogs reacted with contractions to the antigen, while 11 rings from other dogs did not react. Seven sensitized rings were re-challenged after atropine, which significantly prevented the antigen from contracting these rings at a time when antigen contracted 3 non-atropinized, simultaneously tested rings from the same bronchi. Acetylcholine may play a part in the smooth-muscle contraction induced by antigen, or atropine may inhibit early activation of the "arachidonic acid cascade". The findings may be of interest in the interpretation of anti-muscarinic drugs as inhibitors of reflex cholinergic activity versus local anti-allergic effect.

Lung function and bronchial reactivity in six patients with immotile cilia syndrome.

Previous studies of immotile cilia syndrome have shown airway obstruction. The aim of this study was to analyse lung function in such patients before severe chronic obstruction had occurred. Spirometry, lung volumes, pulmonary resistance and static pressure volume diagram were studied in six patients (ages 21-43 years). Closing capacity, the volume of trapped gas and the slope of the alveolar plateau were determined with N2 wash-out tests. Regional ventilation was studied with a gamma camera after inhalation of 99Tcm-tagged dry aerosol. Arterial blood gases were determined at rest and during exercise. Bronchial reactivity was studied with FEV1 before and after inhalation of methacholine aerosol. Five of six patients showed a rather uniform pattern, dominated by signs of "small airway disease" seen in e.g. volumes of trapped gas and closing capacity. Those five patients had uneven ventilation scintiscans and bronchial hyperreactivity. Spirometric findings and lung mechanics were influenced by lung resection, scoliosis and by the lability of bronchial tone. Five patients had normal arterial blood gases at maximum work load. Working capacity was essentially normal in all but one patient, who had a high degree of obstruction. Immotile cilia syndrome is thus compatible with a comparatively well preserved lung function and a normal working capacity far into adult life.