Bronchial Mucosa Of Patients Research Articles

Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma.

The mechanisms contributing to airway wall remodeling in asthma are under investigation to identify appropriate therapeutic targets. Bronchial myofibroblasts would represent an important target because they play a crucial role in the genesis of subepithelial fibrosis, a characteristic feature of the remodeling process, but their origin is poorly understood. We hypothesized that they originate from fibrocytes, circulating cells with the unique characteristic of expressing the hemopoietic stem cell Ag CD34 and collagen I. In this study we show that allergen exposure induces the accumulation of fibrocyte-like cells in the bronchial mucosa of patients with allergic asthma. These cells are CD34-positive; express collagen I and alpha-smooth muscle actin, a marker of myofibroblasts; and localize to areas of collagen deposition below the epithelium. By tracking labeled circulating fibrocytes in a mouse model of allergic asthma, we provide evidence that fibrocytes are indeed recruited into the bronchial tissue following allergen exposure and differentiate into myofibroblasts. We also show that human circulating fibrocytes acquire the myofibroblast phenotype under in vitro stimulation with fibrogenic cytokines that are produced in exaggerated quantities in asthmatic airways. These results indicate that circulating fibrocytes may function as myofibroblast precursors and may contribute to the genesis of subepithelial fibrosis in asthma.

Effects of suplatast tosilate on allergic eosinophilic airway inflammation in patients with mild asthma

Background: Bronchial asthma is a chronic inflammatory disease characterized mainly by infiltration of the airway mucosa by various inflammatory cells, notably eosinophils. TH2-type cytokines are suggested to be deeply involved in the pathogenesis of asthma. Objective: We sought to determine the suppressive effects of suplatast tosilate, an inhibitor of TH2-type cytokines, on eosinophilic inflammation of the bronchial mucosa in patients with mild asthma. Methods: Airway hyperresponsiveness tests, pulmonary function tests, eosinophil measurements in induced sputum, and bronchial mucosa biopsies were performed before and after treatment with suplatast tosilate for 6 weeks in 15 patients with mild asthma and in 13 control patients with mild asthma not receiving suplatast tosilate. This study was performed as a case-controlled open study. Results: In the treatment group a significant improvement in the provocation concentration of histamine was observed (P < .05). Improvements in peak expiratory flow (P < .01) and in symptom score (P < .05) were also noted in the suplatast tosilate–treated group. Moreover, the average number of infiltrating eosinophils and EG2+ cells significantly decreased (both P < .05), as did the ratios of eosinophils and EG2+ cells in sputum (both P < .01). The average number of CD4+ and CD25+ T lymphocytes also decreased (both P < .05). Conclusion: Suplatast tosilate appears to inhibit allergic airway inflammation mediated by TH2-type cytokine and to improve clinical symptoms in patients with mild asthma.

Subepithelial vascular patterns in bronchial dysplasias using a high magnification bronchovideoscope

Background: We have developed a method of high magnification bronchovideoscopy that enables improved observation of subepithelial vascular patterns of the bronchial mucosa. A study was undertaken to investigate the value...

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.

Chronic sinusitis in severe asthma is related to sputum eosinophilia

Background: Chronic rhinosinusitis and asthma are conditions that frequently coexist, particularly in severe asthma. The precise mechanism of the relationship between upper and lower airway inflammation is still a matter of debate. We hypothesized that the extent of inflammation in the nasal mucosa is related to lung function and inflammation in the bronchial mucosa in patients with severe asthma. Objective: We sought to investigate the relationship between sinonasal inflammation as assessed on computed tomography (CT) scanning, lung function, sputum eosinophilia, and nitric oxide (NO) in exhaled air in patients with severe asthma. Methods: Eighty-nine nonsmoking outpatients with severe asthma (29 men and 60 women; mean age 45 years; age range, 18-74 years) were included in this study. CT scans were scored (0-30) by a blinded investigator using a validated method. Lung function, NO in exhaled air, and sputum eosinophils were measured by using standard procedures. Results: CT scans showed abnormalities in 84% of patients. Extensive sinus disease (score 12-30) was found in 24% of patients. There was a significant positive correlation between CT scores and eosinophils in peripheral blood (Rs = 0.46) and induced sputum (Rs = 0.40) and level of exhaled NO (Rs = 0.45, P < .01). CT scores were also positively related to functional residual capacity and inversely related to diffusion capacity, particularly in patients with adult-onset asthma (Rs = 0.47 and Rs = −0.53, respectively). Conclusions: The results of this study show a direct relationship between sinonasal mucosa thickness and bronchial inflammation in severe asthma, particularly in patients with adult-onset disease. Whether sinus disease directly affects the intensity of bronchial inflammation is still an unanswered question. (J Allergy Clin Immunol 2002;109:621-6.)

Inflammation and structural changes in the airways of patients with primary Sjögren's syndrome

The present study aimed to compare the cellular pattern and structural changes in the airways of patients with primary Sjögren's syndrome (pSS) with healthy controls. Bronchial biopsy specimens were obtained from seven subjects with pSS and seven healthy controls. All the patients with pSS had increased bronchial responsiveness to methacholine. In the biopsies inflammatory cells, cytokine-producing cells, tenascin and laminin were visualized by immunostaining. Patients with pSS had a higher number of neutrophils and mast cells than healthy controls, while the number of eosinophils was similar in the two groups. The number of IL-8-positive cells was higher in pSS but the numbers of IL-4-and IL-5-positive cells were not significantly different between pSS and healthy controls. The numbers of T cells in patients with pSS were higher than in healthy controls, while the numbers of CD25-positive cells were similar to the healthy controls. The degree of epithelial integrity in patients with pSS was significantly lower than in the control group and the tenascin and laminin layers were significantly thicker in the pSS group. There was a correlation between the number of mast cells and the thickness of the tenascin and laminin layers in pSS. In conclusion, we found that the cellular pattern in the bronchial mucosa of patients with pSS displayed large numbers of neutrophils, mast cells and T-lymphocytes. These changes in inflammatory cell numbers seemed to relate to the observed increased epithelial damage and structural changes of the subepithelium. The structural findings, but not the pattern of inflammatory cells, are shared with atopic asthma and may relate to the increased bronchial hyper-responsiveness seen in both diseases.

THE CYSTEINYL LEUKOTRIENE D4 RECEPTOR ANTAGONIST MONTELUKAST FOR THE TREATMENT OF INTERSTITIAL CYSTITIS

The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis imply a role for cysteinyl containing leukotrienes as proinflammatory mediators in this disease. We examined the efficacy of the cysteinyl leukotriene 1 receptor antagonist montelukast for treating patients with interstitial cystitis and detrusor mastocytosis. Ten women in whom interstitial cystitis was diagnosed according to National Institute of Diabetes and Digestive and Kidney Diseases criteria and who also had detrusor mastocytosis with a minimum of 28 mast cells per mm.2 muscle tissue were included in this study. Patients received a single dose of montelukast daily for 3 months. The efficacy of treatment was determined by 24-hour urinary frequency, nocturia and pain using visual analog scales. After 1 month of montelukast treatment there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the 3 months of treatment. After 3 months 24-hour urinary frequency had decreased from 17.4 to 12 voidings (p = 0.009), nocturia had decreased from 4.5 to 2.8 (p = 0.019) and pain had decreased from 46.8 to 19.6 mm. on a visual analog scale (p = 0.006). No side effects were observed during treatment. Montelukast treatment resulted in significant improvement in urinary frequency and pain. Its efficacy for decreasing urinary frequency and pain imply a role of leukotriene receptor antagonists for managing interstitial cystitis but further placebo controlled clinical studies are needed.

Basophil recruitment and IL-4 production during human allergen-induced late asthma

Background: Basophils represent an important source of inflammatory mediators and cytokines after IgE-dependent activation in human beings. Objective: To assess the role of basophils in allergic asthma, we measured the number of basophils in the bronchial mucosa and their capacity to express IL-4 mRNA and protein during allergen-induced late asthmatic responses. Methods: Fiberoptic bronchoscopic bronchial biopsies were obtained at 24 hours from sites of segmental bronchial allergen challenge and control sites in 19 patients with atopic asthma and 6 nonatopic healthy volunteers. Basophil numbers were assessed by immunohistochemistry through use of mAb 2D7. IL-4 mRNA–positive cells were detected through use of in situ hybridization and colocalized to basophils through use of sequential immunohistochemistry/in situ hybridization. IL-4 protein was detected and colocalized to basophils through use of dual immunohistochemistry. Results: After allergen challenge, there was an increase in the median number of 2D7-positive basophils per square millimeter in the bronchial mucosa in patients with asthma (0.9 cells/mm2 at baseline to 8.8 cells/mm2 after challenge; P = .002), which also was significantly higher than what was seen in nonasthmatic controls (P = .01). Similarly, IL-4 mRNA– positive cells were increased at 24 hours in patients with asthma (1.4 to 14) in comparison with controls (0 to 0; P = .02). Colocalization studies revealed that 15% and 41% of the basophil population in patients with asthma after allergen-challenge expressed, respectively, IL-4 mRNA and protein. Conversely, 19% of IL-4 mRNA–positive cells and 72% of IL-4 protein–positive cells were accounted for by basophils. Conclusion: After allergen provocation in sensitive patients with atopic asthma, basophils are recruited to the bronchial mucosa and express IL-4 mRNA and protein, which might contribute to local IgE synthesis and/or tissue eosinophilia or other aspects of allergic inflammation during late responses and ongoing asthma. (J Allergy Clin Immunol 2001;108:205-11.)

Inhaled corticosteroids decrease vascularity of the bronchial mucosa in patients with asthma

Increased vascularity in airway mucosa is a distinctive feature of airway remodelling in asthma. While corticosteroids have proved most effective in modifying airway inflammation, the effect of inhaled corticosteroids on increased airway mucosal vascularity in asthmatics has been little studied. We examined the effect of inhaled corticosteroid on airway vascularity in bronchial biopsy specimens taken from asthmatic patients. We studied bronchial biopsies from 28 asthmatic patients before and after treatment with inhaled beclomethasone dipropionate (BDP) 800 microg/daily, or placebo, for 6 months in a double-blind manner. Biopsy specimens were evaluated for number of vessels and percentage of area occupied by vessels, using computerized image analysis after staining for type IV collagen in vessel walls. Specimens were also examined for extent of collagen III in the subepithelial basement membrane. In addition, we compared asthmatic specimens with biopsy specimens taken from non-asthmatic control subjects. There was a significant increase in number of vessels (P < 0.01) and percent vascularity (P < 0.001) in the submucosa of asthmatic patients compared with control subjects. After 6 months of treatment, we observed significant improvements in forced expiratory volume in 1 s (FEV1), FEV1% and airway responsiveness (P < 0.05, each) in the BDP treatment group compared with the placebo group. This was accompanied by significant decreases in both vessel number and percent vascularity in the airways of BDP-treated patients (P < 0.05, each). We also observed a significant correlation between change in percent vascularity and change in collagen III thickness in the BDP-treated patients (rs = 0.90, P < 0.001). Furthermore, the change in percent vascularity was inversely correlated with both FEV1 (rs = -0.49, P < 0.05) and airway responsiveness (rs = -0.36, P < 0.05). These findings suggest that inhaled corticosteroid treatment of asthma reduced airway wall vascularity during airway remodelling.

Increased expression of IL-16 immunoreactivity in bronchial mucosa after segmental allergen challenge in patients with asthma

Background: We have previously shown increased expression of the CD4+ cell chemoattractant IL-16 in bronchial mucosa of patients with asthma. We investigated the effects of allergen challenge on airway IL-16 expression. Methods: We investigated the expression of IL-16 immunoreactivity in bronchial biopsy samples obtained from atopic asthmatic subjects (n = 19) and normal subjects (n = 6) 24 hours after segmental allergen challenge. Control biopsy samples were obtained either at baseline or after diluent challenge. IL-16 expression was correlated to numbers of CD4+ cells, CD25+ cells, and activated eosinophils. IL-16 bioactivity was assessed in bronchoalveolar fluid obtained from patients with asthma. Results: IL-16 expression was higher in control biopsy specimens obtained from subjects with asthma compared with normal subjects (P < .05). In patients with asthma, numbers of IL-16 immunoreactive cells were significantly higher in biopsy specimens obtained after allergen challenge compared with control biopsy specimens (P < .001). Allergen provocation was associated with release of IL-16 in bronchoalveolar fluid in patients with asthma. In normal subjects, there was no difference in the number of IL-16–immunoreactive cells in biopsy specimens obtained after allergen challenge compared with biopsy specimens obtained after diluent challenge. Allergen challenge was associated with an increase in the numbers of EG2+ eosinophils in patients with asthma but not in normal subjects. IL-16 expression correlated with the numbers of CD4+ cells and CD25+ cells after allergen challenge in asthmatic subjects with a provocative concentration required to decrease the FEV1 by 20% of its baseline value (PC20FEV1) < 4 mg/mL. IL-16–immunoreactive cells were identified mainly as T cells and eosinophils in asthmatic subjects after allergen challenge. Conclusion: Endobronchial allergen provocation in atopic asthmatic patients resulted in increased airway expression of IL-16 and release of bioactive IL-16 in airways. IL-16 may contribute to the immunoregulation of the inflammatory infiltrate in the airways in response to antigen. (J Allergy Clin Immunol 2000;106:293-301.)

Histological Examination of Bronchial Mucosa after Photodynamic Therapy Showing no Selectivity of Effect between Tumour and Normal Mucosa

.After the treatment for early stage bronchogenic carcinoma including carcinoma in situ with photodynamic therapy (PDT), the degree of bronchial mucosal damage was studied histologically. The influence of treatment modality on bronchial mucosa was also examined. Few studies of histological changes of bronchial mucosa caused by PDT have been done.The histological specimens of bronchial mucosa in patients who received PDT and had a complete response were reviewed retrospectively. Twenty-three patients with 24 carcinomas including six carcinomas in situ had been treated with PDT using argon dye laser, excimer dye laser with or without additional radiotherapy. The degree of epithelial and subepithelial changes was classified as normal, hyperplasia, metaplasia and as mild, moderate and marked fibrosis, respectively.Subepithelial fibrosis was seen after PDT in almost all cases even when the tumour was entirely superficial to this layer. As a whole, epithelial change was found to be hyperplastic in three and metaplastic in 13 cases. Subepithelial fibrosis were found to be mild in four, moderate in 13, and marked in four cases. No differences were seen between the effects with the excimer and argon dye lasers.As used at present, PDT in the bronchi has no selectivity between normal and tumour tissue but may have advantages over other techniques due to the lack of cumulative toxicity and the excellent healing.

Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma

BACKGROUNDIt has been reported that pranlukast reduces the antigen induced immediate and late phase asthmatic responses, airway hyperreactivity to acetylcholine, and pulmonary eosinophil accumulation in guinea pigs. A study was...

Eotaxin mRNA Expression in Bronchial Mucosa of Patients with Asthma

Background: Asthma is a chronic inflammatory disease of the airways characterized by a marked infiltration of eosinophils in the bronchial mucosa. Asthmatic bronchial mucosa produces many factors described as being chemotactic for inflammatory cells. IL-5, RANTES, and MCP-1 alpha are the chemotactic factors for eosinophils, but their roles are controversial. Recently eotaxin that is a potent eosinophil chemoattractant cytokine was detected in a guinea-pig model of allergic airway inflammation, and human eotaxin was cloned. Eotaxin is a specific chemoattractant for eosinophils, but its role in asthma is not confirmed. We examined the in vivo expression of eotaxin in bronchi of asthmatic patients. Methods : 11 asthmatics and 2 normal controls were enrolled. All subjects were underwent bronchoscopy with bronchial biopsies in 2nd or 3rd carina. RNA extraction from biopsy samples was done by acid-guanidium method. Semi-quantitaive RT-PCR was done for evaluation of eotaxin mRNA expression The extent of eosinophil infiltration was evaluated by counting the eosinophils in submucosa in HPF of microscope. Results : Eotaxin mRNA expressed in symptomatic, uncontrolled asthma. Steroid inhibited expression of eotaxin mRNA in asthma. Expression of eotaxin mRNA correlated with eosinophil infiltration in bronchial tissues. Conclusion: Expression of eotaxin mRNA increases in uncontrolled asthma and eotaxin is involved in the recruitment of eosinophils.

Upregulation of αGM-CSF-receptor in nonatopic asthma but not in atopic asthma

Background: Intrinsic asthma is characterized by an increased number of activated eosinophils and macrophages and an increased expression of the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) in the bronchial mucosa. Objective: This study was carried out to investigate the expression of αGM-CSF receptor (αGM-CSFr) messenger RNA and protein in the bronchial mucosa of patients with intrinsic or atopic asthma and of control subjects and to correlate the expression of αGM-CSFr to the number of EG2 + cells (eosinophils) and CD68 + cells (macrophages) and pulmonary function. Methods: Nineteen patients with stable asthma (9 with atopic and 10 with intrinsic asthma) and 22 normal control subjects (12 atopic and 10 nonatopic subjects) were recruited, and FEV 1 (percent predicted) and PC 20 were measured before bronchoscopy. Endobronchial biopsy specimens were obtained and examined for membrane-bound αGM-CSFr by using in situ hybridization and immunocytochemistry. Results: αGM-CSFr mRNA- and protein-positive cells were identified in biopsy specimens from all four groups studied. There was no significant difference in the number of cells expressing αGM-CSFr mRNA and protein in patients with atopic asthma compared with atopic and nonatopic control subjects. However, the numbers of αGM-CSFr mRNA- and protein-positive cells were significantly higher in nonatopic patients with asthma compared with atopic patients with asthma and atopic and nonatopic control subjects ( p < 0.001). In the patients with intrinsic asthma, the number of αGM-CSFr mRNA-positive cells per millimeter of basement membrane correlated with numbers of CD68 + cells ( r 2 = 0.87, p < 0.001) but not with EG2 + cells, and colocalization studies demonstrated that 80% of the cells expressing αGMCSFr mRNA were CD68 +. The expression of GM-CSF was also significantly increased in patients with intrinsic asthma compared with those with atopic asthma and control subjects ( p < 0.05). In addition, in intrinsic asthma, there was a correlation between αGM-CSFr mRNA and FEV 1 ( r 2 = 0.61, p < 0.05). Conclusion: These results demonstrate that elevated numbers of cells expressing αGM-CSFr can be detected in nonatopic asthma but not in atopic asthma and suggest that this increased expression is predominantly macrophage-associated and may play an important pathophysiologic role in intrinsic asthma. (J Allergy Clin Immunol 1997;99:666-72.)

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.

Influence of allergen avoidance on the eosinophil phase of airway inflammation in children with allergic asthma

BACKGROUND: Exposure to relevant allergens causes an increase in bronchial hyperresponsiveness, as well as an inflammatory reaction at the site of the bronchial mucosa in patients with asthma. OBJECTIVE: The purpose of this study was to determine whether antigen avoidance can exert an antiinflammatory effect on the eosinophil phase of airway inflammation in children with asthma. METHODS: The level of bronchial hyperreactivity and the percentage of eosinophils in sputum samples obtained by inhalation of hypertonic saline solution, were evaluated in a group of asthmatic children allergic to house dust mite before and after a period of antigen avoidance in an Alpine environment (1756 m). RESULTS: At the end of the avoidance period PC 20 increased from a median value (lower and upper quartile: Q1, Q3) of 1.17 (0.74, 4.75) to 3.5 (1.18, 8.87) mg/ml ( p = 0.02), and eosinophil percentage in the sputum decreased from a median value (Q1, Q3) of 14.02 (3.34, 28.24) to 2.08 (0, 7.4) ( p < 0.01). CONCLUSION: A 3-month period of antigen avoidance can significantly reduce the eosinophil phase of airway inflammation, along with bronchial hyperresponsiveness, in patients with asthma. (J A LLERGY C LIN I MMUNOL 1996;97:1079-84.)

CD8 T-cell clones producing interleukin-5 and interferon-gamma in bronchial mucosa of patients with asthma induced by toluene diisocyanate.

The aims of the present study were to determine whether specific in vivo stimulation of asthmatics sensitized with toluene diisocyanate (TDI) induces the activation of T lymphocytes in bronchial mucosa and to characterize their phenotype and cytokine secretion profile. Bronchial biopsies from two subjects with occupational asthma due to TDI were obtained 48 h after an asthmatic reaction induced by an inhalation challenge with TDI and after three months of no exposure to TDI, at the time when the subjects had recovered from their asthma. The fragments of bronchial mucosa were cultured in the presence of interleukin-2 so that the in vivo activated T cells present in the tissue would expand, and T blasts were then cloned under limiting dilution conditions. From the two 48-h specimens, 65 and 63 T-cell clones were obtained. Most of the clones exhibited the CD8 phenotype (82 and 83%). All of the CD8 clones produced interferon-gamma and 44% produced interleukin-5, but only 6% secreted interleukin-4 as well. Three months after the cessation of exposure, growing T cells could not be recovered from bronchial biopsies cultured in interleukin-2. The results suggest that, in sensitized subjects, exposure to TDI induces the activation of a subset of CD8 lymphocytes producing interferon-gamma and interleukin-5.

Mast cells in the airway lumen and bronchial mucosa of patients with chronic bronchitis.

In order to evaluate the degree of mast cell infiltration and determine their granulation state in the airways of patients with chronic bronchitis, bronchoscopy was performed in 25 chronic bronchitis subjects (10 smokers and 15 ex-smokers) with mucoid sputum production and in seven normal nonsmoking control subjects. Bronchoalveolar lavage and bronchial biopsies were examined using histochemical techniques. Subjects with chronic bronchitis had higher numbers of mast cells both in the epithelium (1.22 +/- 1 versus 0.22 +/- 0.2 mast cells per mm) and in the bronchial glands (137.4 +/- 37.9 versus 38 +/- 5.1 mast cells per mm2) than did control subjects (p < 0.01 and p < 0.001, respectively), whereas the numbers of mast cells in bronchoalveolar lavage (0.21 +/- 0.1 versus 0.18 +/- 0.1 mast cells percentage, nonsignificant [NS]) and in the lamina propria (87.5 +/- 66.4 versus 87.2 +/- 61.8 mast cells per mm2, NS) were similar in the two groups. In the smoking group of bronchitics an increase in mast cell numbers was observed in epithelium (1.6 +/- 1.3 versus 0.95 +/- 0.7 mast cells per mm, NS), in lamina propria (112.2 +/- 86.5 versus 71.7 +/- 45.7 mast cells per mm2), and in BAL (0.26 +/- 0.21 versus 0.16 +/- 0.17 mast cell percentage of total cells, NS) in comparison with the ex-smoker's group of bronchitics.(ABSTRACT TRUNCATED AT 250 WORDS)

Activated T-lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma

We have studied the phenotype and activation status of leukocytes in the bronchial mucosa in patients with isocyanate-induced asthma. Fiberoptic bronchial biopsy specimens were obtained from nine subjects with occupational (five toluene- and four methylene diisocyanate-sensitive) asthma, 10 subjects with extrinsic asthma, and 12 nonatopic healthy control subjects. Bronchial biopsy specimens were examined by immunohistology with a panel of monoclonal antibodies and the alkaline phosphatase—antialkaline phosphatase method. There was a significant increase in the number of CD25 + cells (interleukin-2 receptor-bearing cells, presumed “activated” T-lymphocytes; p < 0.01) in isocyanate-induced asthma compared with that of control subjects. There were also significant increases in major basic protein (BMK-13)-positive ( p < 0.02) and EG2-positive ( p < 0.01) cells that represent total and “activated” eosinophil cationic protein—secreting eosinophils, respectively. In agreement with our previous findings, CD25 + ( p < 0.01), BMK-13 ( p < 0.03), and EG2 + ( p < 0.01) cells were also elevated in extrinsic asthma. No significant differences were observed in the numbers of T-lymphocyte phenotypic markers (CD3, CD4, and CD8) between subjects with asthma (isocyanate-induced and extrinsic) and control subjects. Similarly, no significant differences in immunostaining for neutrophil elastase (neutrophils) or CD68 (macrophages) were observed. The results suggest that isocyanate-induced occupational asthma and atopic (extrinsic) asthma have a similar pattern of inflammatory cell infiltrate. The results support the view that T-lymphocyte activation and eosinophil recruitment may be important in asthma of diverse etiology.

Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine 5'-monophosphate in non-atopic asthma.

Inhaled adenosine 5'-monophosphate (AMP) causes bronchoconstriction in atopic asthma, probably after in vivo conversion to adenosine. It has been suggested that adenosine potentiates preformed mediator release from mast cells on the mucosal surface of the airways by interacting with specific purinoceptors, without affecting the release of newly generated mediators. The airway response of nine non-atopic subjects with "intrinsic" asthma to inhaled AMP and the influence of the oral, selective H1 histamine receptor antagonist terfenadine on this response was investigated. The geometric mean provocation concentrations of histamine and AMP required to produce a 20% fall in FEV1 (PC20) were 1.82 and 13 mmol/l. In subsequent placebo controlled time course studies the FEV1 response to a single inhalation of the PC20 histamine was ablated after pretreatment with oral terfenadine 180 mg. This dose of terfenadine caused an 80% inhibition of the bronchoconstrictor response to the PC20 AMP when measured as the area under the time course-response curve and compared with the response to PC20 AMP preceded by placebo. Terfenadine 600 mg failed to increase protection against AMP further, but both doses of terfenadine delayed the time at which the mean maximum fall in FEV1 after AMP was achieved. Terfenadine 180 mg had no effect on methacholine induced bronchoconstriction in the same subjects. These data suggest that inhaled AMP may potentiate the release of preformed mediators from preactivated mast cells in the bronchial mucosa of patients with intrinsic asthma.