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Biomedical subjects

J K Sont

Publications and source records attributed to J K Sont.

At least 19 recordsLinked to original sources
PubMed2003

Superior effect of arthroscopic lavage compared with needle aspiration in the treatment of inflammatory arthritis of the knee.

OBJECTIVES: To compare the duration of symptom relief after arthroscopic lavage versus needle aspiration in gonarthritis. METHODS: A retrospective chart analysis was performed in 50 patients with non-septic inflammatory arthritis of the knee who underwent arthroscopic lavage because of relapsing or persisting arthritis after needle aspiration. The primary outcome measure was the time until symptomatic recurrence of knee synovitis. RESULTS: Needle aspiration was associated with a 3.0 times greater risk of recurrence of arthritis compared with arthroscopic lavage within 12 months (P<0.001, 95% confidence interval 2.1-4.4). Patients with longer disease duration and who had used more disease-modifying anti-rheumatic drugs (DMARDs) had a significantly lower risk of recurrence of arthritis compared with patients with shorter disease duration and a lower number of previous DMARDs (P=0.04 and 0.02 respectively). Corticosteroids augmented the effect of both interventions. CONCLUSIONS: Our results indicate that arthroscopic lavage is an effective therapeutic modality in the treatment of inflammatory arthritis of the knee refractory to joint aspiration, especially in patients with longstanding disease.

Administration, Topical↗
PubMed2002

Rhinovirus infection in nonasthmatic subjects: effects on intrapulmonary airways.

The common cold is a highly prevalent, uncomplicated upper airway disease. However, rhinovirus (RV) infection can lead to exacerbation of asthma, with worsening in airway hyperresponsiveness and bronchial inflammation. The current authors questioned whether such involvement of the intrapulmonary airways is disease specific. Twelve nonatopic, healthy subjects (forced expiratory volume in one second (FEV1) >80% predicted, provocation concentration causing a 20% fall in FEV1 (PC20) >8 mg x mL(-1)) were experimentally infected with RV16. Next to PC20 and the maximal response to methacholine (MFEV1 and MV'40p), the numbers of mucosal inflammatory cells and epithelial intercellular adhesion molecule (ICAM)-1 expression in bronchial biopsies were assessed before and 6 days after RV16 inoculation. RV16 infection induced a small but consistent increase in maximal airway narrowing, without a change in PC20. There was a significant increase in bronchial epithelial ICAM-1 expression after RV16, whereas inflammatory cell counts did not change. Nevertheless, the change in the number of submucosal CD3+ cells was correlated with the change in MV'40p. In conclusion, rhinovirus infection in normal subjects induces a limited, but significant increase in maximal airway narrowing, which is associated with changes in bronchial T-cell numbers. Together with the upregulation of bronchial epithelial intercellular adhesion molecule-1, these findings indicate that, even in healthy subjects, rhinovirus infection affects the intrapulmonary airways.

Adult↗
PubMed2001

Rhinovirus-induced airway inflammation in asthma: effect of treatment with inhaled corticosteroids before and during experimental infection.

Asthma exacerbations are frequently linked to rhinovirus infections. However, the associated inflammatory pathways are poorly understood, and treatment of exacerbations is often unsatisfactory. In the present study we investigated whether antiinflammatory treatment with inhaled corticosteroids prevents any rhinovirus-induced worsening of lower airway inflammation. To that end, we selected 25 atopic patients with mild asthma who underwent experimental rhinovirus 16 (RV16) infection, while receiving double-blind, placebo-controlled treatment with the inhaled corticosteroid budesonide (800 microg twice a day) throughout the study period, starting 2 wk before infection. We assessed inflammatory cell numbers in the bronchial mucosa as obtained by bronchial biopsies 2 d before and 6 d after RV16 infection, and analyzed those in relation to cold symptoms, changes in blood leukocyte counts, airway obstruction, and airway hyperresponsiveness. RV16 colds induced an increase in CD3(+) cells in the lamina propria (p = 0.03) and tended to decrease the numbers of epithelial eosinophils (p = 0.06) in both groups analyzed as a whole. The T cell accumulation was positively associated with cold symptoms. Budesonide pretreatment improved airway hyperresponsiveness (p = 0.02) and eosinophilic airways inflammation (p = 0.04). Yet it did not significantly affect the RV16-associated changes in the numbers of any of the inflammatory cell types. We conclude that RV16 infection by itself induces only subtle worsening of airway inflammation in asthma, which is not improved (or worsened) by inhaled corticosteroids. The latter finding is in keeping with the limited protection of inhaled corticosteroids against acute asthma exacerbations.

Administration, Inhalation↗
PubMed2001

High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy.

OBJECTIVE: To assess the feasibility, safety, and efficacy of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in patients with severe, refractory rheumatoid arthritis (RA). METHODS: Fourteen patients (3 male, 11 female, mean age 43 years, mean disease duration 10 years) with active, destructive, refractory RA entered the study. Autologous hematopoietic stem cells were collected by leukapheresis after mobilization with a single infusion of cyclophosphamide (CYC; 4 gm/m2) and subcutaneous injections of filgrastim (granulocyte colony-stimulating factor). Immunomagnetic selection of CD34+ cells from the leukapheresis products was performed to deplete potentially autoreactive lymphocytes. The conditioning regimen consisted of intravenous administration of high doses of CYC (cumulative dose 200 mg/kg), with subsequent reinfusion of the graft. Patients were monitored for disease activity, disability, adverse effects, and hematopoietic and immunologic reconstitution. RESULTS: All 14 patients completed the mobilization and leukapheresis procedures successfully, and 12 proceeded to receive conditioning and transplantation. Engraftment occurred in all of these patients, with rapid hematologic recovery. No major unexpected toxicity was observed. Marked improvement of disease activity was recorded in 8 of 12 patients at >50% of the visits, with a followup ranging from 7 months to 21 months. The clinical responders included 2 patients who had previously failed treatment with tumor necrosis factor (TNF) blocking agents. CONCLUSION: High-dose chemotherapy followed by autologous HSCT is feasible and safe, and can result in long-term improvement of disease activity in patients whose condition previously did not respond to conventional antirheumatic drugs or TNF blocking agents. The persistence of active disease in some patients may reflect the heterogeneity of the underlying disease process.

Adolescent↗
PubMed2001

Image analysis and quantification in lung tissue.

On 9-10 September 1999, an international workshop on image analysis and quantification in lung tissue was held at the Leiden University Medical Center, Leiden, The Netherlands. Participants with expertise in pulmonary and/or pathology research discussed the validity and applicability of techniques used for quantitative examination of inflammatory cell patterns and gene expression in bronchial or parenchymal tissue in studies focusing on asthma and chronic obstructive pulmonary disease (COPD). Differences in techniques for tissue sampling and processing, immunohistochemistry, cell counting and densitometry are hampering the comparison of data between various laboratories. The main goals of the workshop were to make an inventory of the techniques that are currently available for each of these aspects, and in particular to address the validity and unresolved problems of using digital image analysis (DIA) as opposed to manual scoring methods for cell counting and assessment of gene and protein expression. Obviously, tissue sampling and handling, fixation and (immunohistochemical) staining, and microscope settings, are having a large impact on any quantitative analysis. In addition, careful choices will have to be made of the commercially available optical and recording systems as well as the application software in order to optimize quantitative DIA. Finally, it appears to be of equal importance to reach consensus on which histological areas are to be analysed. The current proceedings highlight recent advances and state of the art knowledge on digital image analysis for lung tissue, and summarize the established issues and remaining questions raised during the course of the workshop.

Animals↗
PubMed2001

Allergen-induced impairment of bronchoprotective nitric oxide synthesis in asthma.

BACKGROUND: Endogenous nitric oxide protects against airway hyperresponsiveness (AHR) to bradykinin in mild asthma, whereas AHR to bradykinin is enhanced by inhaled allergens. OBJECTIVE: Hypothesizing that allergen exposure impairs bronchoprotective nitric oxide within the airways, we studied the effect of the inhaled nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on AHR to bradykinin before and after allergen challenge in 10 subjects with atopic asthma. METHODS: The study consisted of 3 periods (1 diluent and 2 allergen challenges). AHR to bradykinin (PD(20)BK) was examined before and 48 hours after allergen challenge, both after double-blinded pretreatment with L-NMMA or placebo. The accompanying expression of the various NOS isoforms (ecNOS, nNOS, and iNOS) was examined by means of immunohistochemistry in bronchial biopsies obtained after diluent and allergen challenge. RESULTS: After placebo, AHR to BK worsened after allergen challenge in comparison with before allergen challenge (PD(20)BK, 70.8 nmol [range, 6.3-331] and 257 nmol [35.5-2041], respectively; P =.0004). After L-NMMA, preallergen and postallergen PD(20)BK values (50.1 nmol [1.8-200] vs 52.5 nmol [6.9-204]; P =.88) were similarly reduced (P <.01) and not different from the postplacebo/postallergen value (P >.05). After allergen challenge, the intensity of staining in bronchial epithelium decreased for ecNOS (P =.03) and increased for iNOS (P =.009). These changes in immunostaining were correlated with the accompanying worsening in AHR to BK (R(s) = -0.66 and 0.71; P <.04). CONCLUSIONS: These data indicate that allergen exposure in asthma induces increased airway hyperresponsiveness to bradykinin through impaired release of bronchoprotective nitric oxide associated with downregulation of ecNOS. This suggests that new therapeutic strategies towards restoring the balance among the NOS isoforms during asthma exacerbations are warranted.

Adult↗
PubMed2001

High dose chemotherapy followed by autologous peripheral blood stem cell transplantation or conventional pharmacological treatment for refractory rheumatoid arthritis? A Markov decision analysis.

OBJECTIVE: To evaluate the effect of high dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) in comparison to conventional pharmacological therapy in the treatment of patients with refractory, progressively erosive rheumatoid arthritis (RA). METHODS: Decision analysis using a Markov model with a 5.5 year time horizon. Probabilities of transition towards 5 different health states, ranging from 70% improvement to death, were derived from published case reports, patient series, and expert panels. Quality of life (QOL) estimates were obtained from 2 RA clinical trials. Patients were hypothetical cohorts of 50-year-old female patients with progressively erosive, active RA, who failed treatment with methotrexate, combination therapy, and tumor necrosis factor blocking agents. Interventions were HDC + ASCT versus conventional pharmacological treatment with a (combination) therapy of disease modifying antirheumatic drugs. As main outcome measures, we included the number of quality adjusted life years (QALY) after HDC + ASCT compared to conventional therapy. Sensitivity analysis was performed to investigate the influence of treatment related mortality (TRM) and the influence of QOL during HDC + ASCT, and to assess the minimal desired effectiveness of HDC + ASCT for a given TRM of 1% and 10%. RESULTS: HDC + ASCT and conventional pharmacological treatment were equally effective in the base-case analysis (3.48 vs 3.46 QALY). A TRM of less than 3.3% favored HDC + ASCT as the preferred treatment. The analysis showed that when TRM was set at 1%, a relatively short period of efficacy was sufficient to remain the preferred strategy, whereas a TRM of 10% would require a sustained response for several years. CONCLUSION: This model predicted equally favorable effects of HDC + ASCT and conventional therapy in the treatment of refractory RA in the base-case. The minor differences in terms of QALY seem to indicate that clinical decision making should be guided by patient preferences. However, better clinical efficacy might be achieved by adaptation of the treatment regimen of HDC + ASCT and patient selection. The model supports the need for randomized clinical trials and may contribute to an optimal study design.

Antirheumatic Agents↗
PubMed2000

Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD.

Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death, with cigarette smoking among the main risk factors. Hallmarks of COPD include chronic airflow obstruction and chronic inflammation in the airway walls or alveolar septa. An earlier study reported elevated numbers of macrophages and mast cells within the bronchiolar epithelium in smokers with COPD, compared with smokers without. Since specific chemokines may be involved in this influx, the in situ protein and mRNA expression of monocyte chemoattractant protein 1 (MCP-1) and of interleukin 8 (IL-8) were studied in tumour-free peripheral lung tissue resected for lung cancer of current or ex-smokers with COPD (FEV(1)<75%; n=14) and without COPD (FEV(1)>84; n=14). MCP-1 was expressed by macrophages, T cells, and endothelial and epithelial cells. Its receptor, CCR2, is expressed by macrophages, mast cells, and epithelial cells. IL-8 was found in neutrophils, epithelial cells, and macrophages. In subjects with COPD, semi-quantitative analysis revealed 1.5-fold higher levels of MCP-1 mRNA and IL-8 mRNA and protein in bronchiolar epithelium (p<0.01) and 1.4-fold higher levels of CCR2 in macrophages (p=0.014) than in subjects without COPD. The bronchiolar epithelial MCP-1 mRNA expression correlated with both CCR2 expression on macrophages and mast cells (p<0.05) and the numbers of intra-epithelial macrophages and mast cells (p<0.04). The epithelial IL-8 expression did not correlate with the numbers of neutrophils, macrophages, CD45RO+, CD8+, or mast cells. These data suggest that MCP-1 and CCR2 are involved in the recruitment of macrophages and mast cells into the airway epithelium in COPD.

Adult↗
PubMed1999

Ozone-induced inflammation assessed in sputum and bronchial lavage fluid from asthmatics: a new noninvasive tool in epidemiologic studies on air pollution and asthma.

We investigated correlations between ozone-induced increases in inflammatory markers in induced sputum and in bronchial lavage fluid. Sixteen volunteers with intermittent asthma participated in a placebo-controlled parallel study with two exposures. Six days before and 16 h after the first exposure to ozone (0.4 ppm during 2 h) sputum was induced with hypertonic saline. This resulted in a significant increase in the sputum levels of eosinophil cationic protein (ECP; 1.8-fold; p = .03), neutrophil elastase (5.0-fold; p = .005) and the total cell number (1.6-fold; p = .02). After 4 weeks, a second exposure was randomized for air or ozone. Six days before and 16 h after the second exposure a bronchial lavage was performed. ECP values in sputum and in bronchial lavage fluid obtained after ozone correlated significantly (Rs = .79; p = .04), as did interleukin-8 (IL-8) values (Rs = .86; p = .01), and the percentage eosinophils (Rs = .89; p = .007). Moreover, the ozone-induced changes in percentage eosinophils observed in sputum and lavage fluid were highly correlated (Rs = .93; p = .003). In conclusion, changes in eosinophils, IL-8, and ECP markers induced by ozone and measured in sputum reflect the inflammatory responses in the lower airways of asthmatics, and may provide a noninvasive tool in epidemiologic studies on air pollution and asthma.

Adult↗
PubMed1999

How do we monitor asthma control?

The present consensus on asthma management includes avoidance of triggers, education, regular follow-up, and an action plan that relies on symptoms and lung function measurements for the monitoring of disease severity. Inclusion of objective measurements for monitoring seems to be important because patients and physicians may not always recognize asthma symptoms or their severity. However, the additional value of monitoring peak flow and symptoms in guiding asthma therapy has not been well established. Furthermore, it can be questioned whether a treatment strategy which is solely based on optimizing symptoms and lung function leads to optimal control of asthma in each individual patient, since airway hyperresponsiveness (AHR) and airways inflammation may persist. The chronicity of such abnormalities may lead to airways remodelling, thereby worsening the long-term outcome of asthma. It has been shown that AHR provides prognostic information on asthma control, because it can serve as a valuable noninvasive surrogate marker of airways inflammation when added to the guides of asthma therapy. A limited increase in dose of inhaled steroids, instead of applying an increased dose indiscriminately, can be successfully tailored to the needs of the individual patient based on the degree of AHR. Such a strategy leads to both a better clinical outcome and a better histologic outcome. The present worldwide effort is to find alternative markers of airways inflammation in asthma that can be easily implemented in routine practice. In the near future, longitudinal studies will determine which parameter is potentially most useful in guiding asthma management.

Adrenal Cortex Hormones↗
PubMed1999

Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.

According to international guidelines, the level and adjustment of antiinflammatory treatment for asthma are based solely on symptoms and lung function. We investigated whether a treatment strategy aimed at reducing airway hyperresponsiveness (AHR strategy) in addition to the recommendations in the existing guidelines (reference strategy) led to: (1) more effective control of asthma; and (2) greater improvement of chronic airways inflammation. To accomplish this, we conducted a randomized, prospective, parallel trial involving 75 adults with mild to moderate asthma who visited a clinic every 3 mo for 2 yr. At each visit, FEV1 and AHR to methacholine were assessed, and subjects kept diaries of symptoms, beta2-agonist use, and peak expiratory flow (PEF). Medication with corticosteroids (four levels) was adjusted according to a stepwise approach (reference strategy), to which four severity classes of AHR were added (AHR strategy). At entry and after 2 yr, bronchial biopsies were obtained by fiberoptic bronchoscopy. Patients treated according to the AHR strategy had a 1.8-fold lower rate of mild exacerbations than did patients in the reference strategy group (0. 23 and 0.43 exacerbation/yr/patient, respectively). FEV1 also improved to a significantly greater extent in the AHR strategy group (p </= 0.05). In bronchial biopsies this was accompanied by a greater reduction in thickness of the subepithelial reticular layer in the AHR strategy group than in the reference strategy group (mean difference [95% confidence interval (CI): 1.7 micrometers (0.2 to 3.1) micrometers]). The changes in AHR in both strategy groups were correlated with eosinophil counts in the biopsies (r = -0.48, p = 0.003). We conclude that reducing AHR in conjunction with optimizing symptoms and lung function leads to more effective control of asthma while alleviating chronic airways inflammation. This implies a role for the monitoring of AHR or other surrogate markers of inflammation in the long-term management of asthma.

Administration, Inhalation↗
PubMed1998

Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease.

Chronic airways inflammation is one of the features of chronic obstructive pulmonary disease (COPD). We demonstrated previously that bronchiolar epithelium in COPD contains increased numbers of macrophages and mast cells. Transforming growth factor beta1 (TGF-beta1) may be involved in this influx because it has chemotactic activity for macrophages and mast cells. In this study, we examined expression patterns of TGF-beta1, TGF-beta receptors type I and II (TGF-betaRI and TGF-betaRII) by immunohistochemistry and mRNA in situ hybridization in peripheral lung tissue of 14 current or ex-smokers with COPD (FEV1 < 75%) and 14 without COPD (FEV1 > 84%). In both groups, TGF-beta1 and its receptors are present in airway and alveolar epithelial cells, airway and vascular smooth muscle cells, and tissue and alveolar CD68(+) cells (considered herein to be macrophages). In subjects with COPD, a semiquantitative analysis revealed approximately twofold higher levels of TGF-beta1 mRNA and protein in bronchiolar and alveolar epithelium (p < 0.02) as compared with subjects without COPD. With regard to bronchiolar epithelial cells, we found a significant correlation between TGF-beta1 mRNA and protein expression (r = 0.62; p < 0.002), and between the FEV1 of all subjects together and TGF-beta1 protein (r = -0.60; p < 0.0002) and mRNA (r = -0.67; p < 0. 002) levels. The epithelial expression of TGF-beta1 mRNA and TGF-beta1 protein correlates with the number of intraepithelial macrophages (both: r = 0.44; p < 0.03) whereas intraepithelial mast cell numbers correlate with epithelial TGF-beta1 mRNA expression. These data suggest a role for TGF-beta1 in recruiting macrophages into the airway epithelium in COPD.

Adult↗
PubMed1998

Assessing the effect of deep inhalation on airway calibre: a novel approach to lung function in bronchial asthma and COPD.

Bronchoconstriction in bronchial asthma and chronic obstructive pulmonary disease (COPD) may be due to decreased airway calibre and/or to the inability of the airways to distend after a deep inhalation (DI). The purpose of this review is to discuss the physiological and clinical relevance of this latter mechanism. During induced constriction, DI shows remarkable bronchodilatation in normal subjects, but a blunted or null effect in asthmatics. In contrast, during spontaneous bronchospasm DI tends to decrease airway calibre. From a functional point of view, airway inflammation, remodelling, and peripheral bronchoconstriction could prevent airway smooth muscle from stretching. Therapeutic intervention improving lung function may change the response to DI. For example, bronchodilators allow expiratory airflow before DI to increase more than after DI, because of decreased bronchial hysteresis. This suggest that bronchodilation might be systematically underestimated from parameters derived from maximal expiratory manoeuvres. Inhaled corticosteroids tend to increase the dilator effect of DI, likely due to decreased bronchial and peribronchial oedema. In conclusion, measuring the effects of deep inhalation on lung function is an easy and simple test able to evaluate the structural changes occurring in the airways and to monitor the effectiveness of therapy.

Airway Resistance↗
PubMed1997

Sample size estimation in studies monitoring exercise-induced bronchoconstriction in asthmatic children.

BACKGROUND: The repeatability of the response to standardised treadmill exercise testing using dry air and monitoring of heart rate in asthmatic children suffering from exercise-induced bronchoconstriction (EIB) has not been well established. METHODS: Twenty seven asthmatic children with known EIB performed standardised exercise testing twice within a period of three weeks. The tests were performed on a treadmill while breathing dry air. During both tests heart rate had to reach 90% of the predicted maximum. Response to exercise was expressed as % fall in forced expiratory volume in one second (FEV1) from baseline and as area under the curve (AUC) of the time-response curve. RESULTS: The intra-class correlation coefficients for % fall and AUC (log-transformed) were 0.57 and 0.67, respectively. From these data, power curves were constructed that allowed estimations to be made of sample sizes required for studies of EIB in children. These indicated that, if a drug is expected to reduce EIB by 50%, as few as 12 patients would be sufficient to demonstrate this effect (90% power) using a parallel design study. CONCLUSIONS: Standardised exercise testing for EIB using dry air and monitoring of heart rate is adequately repeatable for use in research and clinical practice in children with asthma.

Adolescent↗
PubMed1997

The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma.

The cysteinyl leukotriene LTE4 has been shown to induce airway eosinophilia in asthmatics in vivo. This phenomenon has not yet been reported for LTD4. Hence, we examined the effect of inhaled LTD4 and a control bronchoconstrictor agent, methacholine, on cell differentials in hypertonic saline-induced whole sputum samples of 12 nonsmoking atopic asthmatic subjects (three women, nine men; 21 to 29 yr of age; FEV1, 74 to 120% pred; PC20FEV1 methacholine < 9.6 mg/ml). The study had a cross-over, placebo-controlled design consisting of 4 d separated by > or = 1 wk. On each randomized study day, the subjects inhaled five serial doses of either LTD4 (mean cumulative concentration: 95.7 microM) or methacholine (mean cumulative concentration: 542 mM) or five doses of their respective diluents (PBS/ethanol or PBS). The airway response was measured by FEV1, followed by sputum induction with 4.5% NaCl, 4 h postchallenge. Inflammatory cells (> or = 250) were counted twice on coded cytospins and expressed as percentages of nonsquamous cells. There was no significant difference in the maximal percent fall in FEV1 from baseline between LTD4 (mean +/- SEM, 49.5 +/- 4.4% fall) and methacholine (mean +/- SEM, 55.9 +/- 3.4% fall) (p = 0.11). LTD4 induced a significant increase in the percentage of sputum eosinophils as compared with its diluent (mean +/- SD, 26.6 +/- 21.3% and 10.2 +/- 8.8%, respectively; p = 0.025), whereas a similar trend for methacholine failed to reach significance (mean +/- SD, 19.1 +/- 22.9% and 7.8 +/- 5.8%, respectively; p = 0.11). There was no significant difference in the changes in the percentage of sputum eosinophils between LTD4 and methacholine (mean difference +/- SD, 7.5 +/- 12.5% eosinophils; p = 0.09). We conclude that LTD4 induces eosinophilia in sputum of asthmatic subjects 4 h after inhalation. Our data suggest that LTD4 recruits eosinophils into the airways of asthmatics in vivo, possibly by virtue of direct or indirect chemotactic properties, whereas an additional effect of vigourous airway narrowing per se cannot be excluded.

Administration, Inhalation↗
PubMed1997

Enhanced expression of neutral endopeptidase (NEP) in airway epithelium in biopsies from steroid- versus nonsteroid-treated patients with atopic asthma.

The expression of the endogenous neuropeptide-degrading enzyme, neutral endopeptidase (NEP; CALLA, CD10, E.C.3.4.24.11) on cultured human airway epithelial cells can be upregulated by corticosteroids. We examined whether NEP expression in the airway epithelium or lamina propria in bronchial biopsies is enhanced in atopic asthmatics on regular inhaled steroids as compared with those without steroid treatment. Forty nonsmoking adults (age 19 to 48 yr) with mild to moderate asthma (forced expiratory volume in 1 s > or = 50% pred., histamine PC20 range 0.02 to 7.6 mg/ml) with (n = 23) or without (n = 17) regular inhaled steroids treatment entered the study. Biopsies were taken at (sub)segmental level from the right lower lobe, the middle lobe, and the main carina. Immunohistochemical staining was performed on cryostat sections using the VIL-A1 monoclonal antibody against CD10 (NEP). Intra- and inter-observer repeatability of a semiquantitative scoring method was good as assessed by weighted kappa (kappa(w) ranging from 0.66 to 0.81). In the airway epithelium, NEP-positive sites were within the basal layer and, in contrast with studies applying other antibodies, also at apical sites and within the lamina propria. In both the epithelium and lamina propria, NEP expression was not significantly different between the three biopsy sites (Friedman's nonparametric two-way analysis of variance; P > 0.68), nor was expression in the lamina propria associated with inhaled steroid usage (Mann-Whitney U test; P = 0.98). However, NEP expression was significantly enhanced in the airway epithelium in patients using inhaled steroids as compared with nonsteroid users (mean rank: 23.4 and 15.5, respectively; P = 0.02). Among nonsteroid-using subjects, NEP expression was related to symptoms and the methacholine PC20 (Rs: -0.69 and 0.49, respectively; P < or = 0.04). We conclude that the expression of NEP is enhanced in airway epithelium in bronchial biopsy specimens from patients with atopic asthma who are regularly using inhaled steroids as compared with patients who do not. This fits the hypothesis that the anti-inflammatory effect of corticosteroids within the airways is partially mediated by the upregulation of the endogenous neuropeptide-degrading enzyme NEP.

Adrenergic beta-Agonists↗