Decreased expression of angiotensin-converting enzyme in the airway epithelium of asthmatic subjects is associated with eosinophil inflammation.

BACKGROUND: Angiotensin-converting enzyme (ACE) is a peptidase involved in the metabolism of several bioactive peptides. It may be involved in the airway inflammation and hyperresponsiveness that occur in asthma. OBJECTIVE: We studied the expression of ACE in the airway mucosa of normal and asthmatic subjects and assessed the relationship between ACE expression and airway inflammation and bronchial hyperresponsiveness in asthma. METHODS: We used immunohistochemistry to study the ACE expression and airway inflammation in bronchial biopsy samples obtained by fiberoptic bronchoscopy from 20 asthmatic subjects randomly assigned to groups treated with (n = 10) or without inhaled corticosteroids (n = 10) and from normal subjects (n = 10). Airway response to methacholine and bradykinin was also determined for all subjects. RESULTS: In normal subjects ACE was present in the surface epithelium, the endothelial cells of the lamina propria, and the submucosal glands, in which ACE was found in seromucous cells and in secreted mucus. ACE was not detected in smooth muscle cells and in most of the endothelial cells of the vascular network surrounding the glands. ACE was absent or present at lower levels in the surface epithelium of asthmatic subjects not treated with corticosteroids compared with those treated with corticosteroids and the control group. In asthmatic subjects low levels of ACE in the epithelium were associated with larger numbers of eosinophils in the epithelium and lamina propria. There was no relationship between ACE levels in the airway mucosa and airway responsiveness to methacholine and bradykinin. CONCLUSION: ACE expression is decreased in the epithelium of asthmatic patients and is associated with increased eosinophil inflammation.

Airway responsiveness to bradykinin is related to eosinophilic inflammation in asthma.

We investigated the relationship between airway inflammation and airway responsiveness, as assessed by PD15, to methacholine and to bradykinin in asthmatic patients. Bronchoalveolar lavage (BAL), bronchial biopsies, and methacholine and bradykinin challenges were performed in 18 nonsmoking subjects with mild or moderate perennial asthma. Bradykinin PD15 correlated negatively with eosinophil count in BAL (p < 0.05), in the epithelium (p < 0.05), in the lamina propria (p = 0.02) and in the total submucosa (p < 0.01). Conversely, no significant correlation existed between airway responsiveness to methacholine and eosinophil count in BAL or in airway mucosa. Airway responsiveness to either agonist did not correlate with the thickness of the basement membrane, the shedding of the airway epithelium, the count of lymphocytes in the airway mucosa, or the percentage of neutrophils, lymphocytes, and macrophage in BAL. The presence of degranulated eosinophils was associated with an increased number of eosinophils in the airway epithelium (p = 0.04), in the lamina propria (p = 0.03), in the total submucosa (p = 0.02), and with increased airway responsiveness to bradykinin (p < 0.02). We conclude that in asthmatic patients, airway responsiveness to bradykinin but not to methacholine is related to the magnitude of eosinophilic inflammation in the airway mucosa.

Perception of bronchial obstruction in asthmatic patients. Relationship with bronchial eosinophilic inflammation and epithelial damage and effect of corticosteroid treatment.

We studied the perception of bronchoconstriction in asthmatic subjects who were randomly treated with inhaled beta 2 agonist given either alone (n = 9) or associated with inhaled corticosteroids (n = 9). Methacholine and bradykinin challenges, bronchoalveolar lavage, and bronchial biopsies were performed in all subjects. After each dose of agonist, breathlessness was assessed using a visual analog scale (VAS) and the forced expiratory volume in 1 s (FEV1) was measured. The relationship between VAS scores and FEV1 and the slope of the regression line of VAS scores on the corresponding FEV1 (VAS/FEV1 slope) were analyzed for each agonist. Subjects without corticosteroids had good perception of methacholine but poor perception of bradykinin-induced bronchoconstriction. In subjects with corticosteroids, bronchoconstriction was well perceived whatever the agonist. VAS/FEV1 slopes for bradykinin but not for methacholine correlated negatively with the magnitude of eosinophilic inflammation in airway mucosa. VAS/FEV1 slopes for each agonist correlated positively with the percentage of basement membrane covered by airway epithelium. We conclude that in asthmatic patients perception of bronchoconstriction is related to eosinophilic inflammation and to epithelial damage in airways and that corticosteroid treatment is associated with improved perception of bronchoconstriction induced by bradykinin, a mediator endogenously produced in asthma.

Inhaled beta adrenergic agonists and inhaled steroids in the treatment of asthma.

In summary, inhaled steroids are the treatment to be preferred for patients requiring maintenance therapy with steroids, since they cause a dramatic fall in sensitivity and reactivity of bronchial response, improve lung function to normal, reduce the diurnal variation in peak expiratory flow rates, and markedly reduce symptoms. Nevertheless they must be given at adequate dosage for a long time, associated with inhaled beta-agonists, and in more severe asthma with short courses of oral steroids.

Alveolar macrophages in idiopathic pulmonary fibrosis have glucocorticoid receptors, but glucocorticoid therapy does not suppress alveolar macrophage release of fibronectin and alveolar macrophage derived growth factor.

Although glucocorticoids are the most widely used therapeutic modality in the treatment of idiopathic pulmonary fibrosis (IPF), the administration of these agents infrequently arrests the progressive fibrosis of this disorder. In this context, the present study was designed to determine if the lack of effect of glucocorticoid therapy in IPF could be explained, in part, by a lack of effect of glucocorticoids on alveolar macrophage release of fibronectin and alveolar macrophage derived growth factor (AMDGF), mediators thought to play a role in the accumulation of fibroblasts associated with the fibrosis of this disease. Patients with IPF were studied in 2 groups, those receiving glucocorticoid therapy and those not receiving therapy. The release of fibronectin by alveolar macrophages of IPF patients was elevated compared to release of fibronectin from alveolar macrophages obtained from normal volunteers (p less than 0.01). However, the release of fibronectin was no different in treated and untreated patients with IPF (p greater than 0.2). Like fibronectin, the release of AMDGF by alveolar macrophages of IPF patients was elevated compared to release of AMDGF from alveolar macrophages obtained from normal volunteers (p less than 0.01), but there was no difference in treated and untreated IPF patients (p greater than 0.2). Sequential evaluation of IPF patients before and after glucocorticoid therapy demonstrated no impact of glucocorticoid therapy on alveolar macrophage release of fibronectin and AMDGF. The inability of glucocorticoids to suppress fibronectin and AMDGF release was not due to a lack of glucocorticoid receptors in IPF patients because alveolar macrophages from patients and from normal volunteers bound glucocorticoids similarly.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypersensitivity pneumonitis in man. Light- and electron-microscopic studies of 18 lung biopsies.

Light- and electron-microscopic changes produced by hypersensitivity pneumonitis were analyzed in open lung biopsies taken from 18 patients with chronic forms of the disease. The main changes observed were: alveolitis (both luminal and mural), granulomas, intraalveolar buds, and interstitial fibrosis. The cells infiltrating the alveolar walls were mainly lymphocytes. Occasionally these lymphocytes presented irregularities in the contours of the nuclear membranes and resembled Sézary cells. In one patient, a few lymphocytes were found that resembled "hand-mirror" cells. Intraalveolar macrophages often had a foamy appearance. Granulomas, present in two-thirds of the patients, differed in several respects from those in sarcoidosis: they were smaller, more loosely arranged, and poorly limited; they had a higher content of lymphocytes; and they were located more frequently in alveolar tissue than in the vicinity of bronchioles and vessels. Intraalveolar buds, also present in about two thirds of the patients, were composed mainly of fibroblasts, myofibroblasts, and macrophages in a loose connective tissue that was rich in proteoglycan material. Capillaries and epithelial cells were rarely seen in buds. Alveolar buds appear to develop by a process of disruption of the epithelial lining layer, due to alveolitis, followed by intraalveolar exudation and by subsequent intraalveolar migration of connective tissue cells interacting with macrophages. Severe fibrotic and alveolar epithelial changes were observed in four patients; milder changes were frequent in most other patients. It is concluded that hypersensitivity pneumonitis usually has distinctive morphologic features; these may help to distinguish the resultant pulmonary fibrosis from that due to other causes.