Biomedical subjects

P H Howarth

Publications and source records attributed to P H Howarth.

At least 19 recordsLinked to original sources

PubMed2005

Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma.

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNFalpha is generated in excess. By contrast, asthma is regarded as a Th2 type disorder, especially when associated with atopy. However, as asthma becomes more severe and chronic, it adopts additional characteristics including corticosteroid refractoriness and involvement of neutrophils suggestive of an altered inflammatory profile towards a Th1 type response, incriminating cytokines such as TNFalpha. METHODS: TNFalpha levels in bronchoalveolar lavage (BAL) fluid of 26 healthy controls, 42 subjects with mild asthma and 20 with severe asthma were measured by immunoassay, and TNFalpha gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma. The cellular localisation of TNFalpha was assessed by immunohistochemistry. An open label uncontrolled clinical study was then undertaken in 17 subjects with severe asthma to evaluate the effect of 12 weeks of treatment with the soluble TNFalpha receptor-IgG1Fc fusion protein, etanercept. RESULTS: TNFalpha levels in BAL fluid, TNFalpha gene expression and TNFalpha immunoreative cells were increased in subjects with severe corticosteroid dependent asthma. Etanercept treatment was associated with improvement in asthma symptoms, lung function, and bronchial hyperresponsiveness. CONCLUSIONS: These findings may be of clinical significance in identifying TNFalpha as a new therapeutic target in subjects with severe asthma. The effects of anti-TNF treatment now require confirmation in placebo controlled studies.

Adult↗

PubMed2005

Nasal lavage fluid concentrations of eotaxin-1 (CCL11) in naturally occurring allergic rhinitis: relationship to disease activity, nasal luminal eosinophil influx, and plasma protein exudation.

BACKGROUND: Eotaxin-1 (CCL11) is a CC chemokine whose nasal eosinophilic chemotactic activity in vivo and in vitro has been demonstrated primarily using nasal allergen challenge models. The extension of these challenge findings to the in vivo setting has been limited. OBJECTIVE: To obtain nasal lavage fluid from volunteers with perennial and seasonal (in- and out-of-season) allergic rhinitis (AR) and non-atopic non-rhinitic controls for the measurement of eotaxin-1 concentrations and to relate these findings to the symptomatic disease severity, the percentage of lavage eosinophils, and to alpha(2)-macroglobulin (alpha(2)-MG) lavage concentrations, as a marker of vascular permeability and an index of airway inflammation. METHODS: Thirty-seven volunteers with AR (16 seasonal and 21 perennial) and 20 non-atopic non-rhinitic volunteers were recruited and phenotyped. Nasal lavage fluid was obtained by standardized protocol. The nasal lavage fluid concentrations of eotaxin and alpha(2)-MG were measured by ELISA, and differential cell counts performed on cytospins. RESULTS: Eotaxin-1 nasal lavage fluid concentrations were significantly higher in both the perennial and seasonal (in-season) AR groups compared with the controls, and significantly related to the severity of symptom expression and to the percentage of lavage eosinophils. The lavage eosinophil counts were significantly higher in both the symptomatic rhinitis groups compared with the control groups and correlated with the lavage concentrations of alpha(2)-MG. alpha(2)-MG levels were significantly increased in seasonal (in-season) rhinitics compared with both non-atopic controls and seasonal (out-of-season) rhinitics. A significant correlation was observed between the levels of alpha(2)-MG and levels of eotaxin in the symptomatic allergic rhinitic groups. CONCLUSIONS: This study clearly demonstrates the relevance of eotaxin-1 to the pathogenesis of naturally occurring AR.

Adult↗

PubMed2005

The novel use of the human nasal epithelial cell line RPMI 2650 as an in vitro model to study the influence of allergens and cytokines on transforming growth factor-beta gene expression and protein release.

BACKGROUND: The epithelial accumulation of mast cells is a feature of allergic rhinitis and this has been linked to the expression of the known mast cell chemoattractant transforming growth factor-beta (TGF-beta) at this site. Little is known concerning the regulation of TGF-beta gene expression or protein release by nasal epithelial cells. To address this we have utilized the RPMI 2650 human nasal epithelial cell line, which has some features that closely resemble normal nasal epithelium and has been reported to secrete a TGF-beta-like molecule. OBJECTIVES: To investigate the regulation of TGF-beta gene expression and protein secretion in RPMI 2650 nasal epithelial cells following exposure to allergens (house dust mite (HDM) and grass pollen) and mast cell associated T-helper type 2 (Th2) cytokines (IL-4, IL-13, and TNF-alpha). Methods Light and scanning electron microscopy was used to evaluate the morphology of RPMI 2650 cells in culture, enzyme-linked immunosorbent assay was used to investigate their TGF-beta secretory capacity and the identification of the TGF-beta isotype(s) involved, flow cytometry was used to demonstrate the presence of TGF-beta receptors on the RPMI 2650 cells, and the quantitative real-time TaqMan PCR was used to measure TGF-beta gene expression. RESULTS: TGF-beta(2) was identified as the main isotype secreted by the RPMI 2650 cells. HDM allergens and TNF-alpha increased both TGF-beta gene expression and protein release from these cells, whereas grass pollen, IL-4, and IL-13 were without effect. CONCLUSIONS: The RPMI 2650 nasal epithelial cell line represents a valid in vitro model to evaluate the regulation of TGF-beta biology. In this system HDM allergens have stimulatory activity that is fundamentally different from that of grass pollen allergens, and the Th2 cytokines IL-4 and IL-13 are without effect. The ability of TNF-alpha to up-regulate both TGF-beta gene expression and protein release indicates that mast cell-epithelial interactions concerning TGF-beta are bi-directional and this may be fundamental to epithelial immunoregulation. The availability of a model system, such as the RPMI 2650 cells, will enable the early evaluation of future novel and targeted interventions directed toward the aberrant responses of upper airway structural cells.

Allergens↗

PubMed2005

Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium.

A disease-related, corticosteroid-insensitive increase in the expression of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium has been shown previously by the current authors. To determine whether this is associated with enhanced intracellular signalling, the aim of this study was to evaluate epithelial tyrosine phosphorylation. Bronchial biopsies were analysed for the presence of phosphotyrosine by immunohistochemistry. Bronchial epithelial cells were exposed to EGF, hydrogen peroxide or tumour necrosis factor-alpha in vitro for measurement of tyrosine phosphorylated signalling intermediates and interleukin (IL)-8 release. Phosphotyrosine was increased significantly in the epithelium of severe asthmatics when compared with controls or mild asthmatics; however, in mild asthma, phosphotyrosine levels were significantly decreased when compared with controls. There was no significant difference between phosphotyrosine levels before or after 8 weeks of treatment with budesonide. Stimulation of bronchial epithelial cells resulted in tyrosine phosphorylation of several proteins, including EGFR, Shc and p42/p44 mitogen-activated protein kinase. In the presence of salbutamol, a transient partial suppression of EGFR phosphorylation occurred, whereas dexamethasone was without effect. Neither salbutamol nor dexamethasone inhibited EGF-stimulated IL-8 release. These data indicate that regulation of protein tyrosine kinase activity is abnormal in severe asthma. The epidermal growth factor receptor and/or other tyrosine kinase pathways may contribute to persistent, corticosteroid-unresponsive inflammation in severe asthma.

Administration, Inhalation↗

PubMed2004

Epithelial expression and release of FGF-2 from heparan sulphate binding sites in bronchial tissue in asthma.

BACKGROUND: The most characteristic structural change evident in endobronchial biopsies in asthma, even in mild disease, is subepithelial collagen deposition within the lamina reticularis. This has been associated with progressive loss of lung function and the persistence of airway hyperresponsiveness, and has been linked to airway fibroblast proliferation. A potent fibroproliferative factor in bronchoalveolar lavage fluid in asthma is fibroblast growth factor-2 (FGF-2). FGF-2 is a member of a family of heparin binding growth factors that bind to heparan sulphate proteoglycans (HSPG), an important determinant of FGF-2 activity. This study compared the level of expression and distribution of FGF-2 in relation to HSPG in bronchial tissue from normal and asthmatic subjects. METHODS: The distribution of FGF-2 and HSPG in intact and cleaved forms in endobronchial biopsies from normal and asthmatic subjects was examined using an immunohistochemical approach. A novel ELISA based method was developed to detect solubilisation of FGF-2 following addition of heparin and heparitinase to bronchial tissue slices. RESULTS: Immunohistochemical analysis showed that FGF-2 was co-localised to HSPG in epithelial and endothelial basement membranes. Epithelial FGF-2, but not HSPG, was significantly more abundant in patients with mild asthma than in normal subjects. In vitro experiments indicated that FGF-2 was released from binding sites in the tissue by heparin and heparitinase I. CONCLUSIONS: FGF-2 is bound by HSPG in bronchial tissue. The mast cell, through the release of heparin and endoglycosidase, may make a unique contribution to tissue remodelling in allergic asthma.

Adult↗

PubMed2004

Endobronchial ultrasound to assess airway wall thickening: validation in vitro and in vivo.

Endobronchial ultrasound (EBUS) allows identification of airway wall structures and could potentially be utilised for in vivo studies of airway thickening in asthma. The present study investigated whether inflation of the fluid-filled balloon sheath over the transducer (necessary to provide sonic coupling with the airway wall) influenced in vitro measurements. In vivo comparability of EBUS with high resolution computed tomography scanning (HRCT), an established method for measuring wall thickness, was determined in control subjects. The airway diameter and wall thickness were studied using EBUS in 24 cartilaginous airways obtained from four sheep, before and after balloon sheath inflation during immersion in saline. To assess EBUS versus HRCT comparability of airway measures in vivo, 12 control subjects underwent imaging of the posterior basal bronchus of the right lower lobe by both techniques. Intra- and interobserver agreement were also assessed. Results with and without the balloon sheath gave comparable measures of airway internal diameter and wall thickness in vitro. Statistical analysis showed agreement between EBUS and HRCT, and intra- and interobserver variability in vivo. The current study concludes that endobronchial ultrasound, which does not present a radiation risk, could be utilised in the in vivo study of cartilaginous airway wall remodelling in respiratory diseases, such as asthma.

Adult↗

PubMed2003

Allergic rhinitis: past, present and the future.

Allergic rhinitis represents a global health issue affecting between 10% to 25% of the world population, with increasing prevalence over the last decade. Although often trivialized by patients and doctors, allergic rhinitis is a significant cause of morbidity, in addition to its substantial economic impact. While allergic rhinitis is an inflammatory disorder of the upper airways, inflammation alone is insufficient to explain the chronic nature of the disease. An exciting concept which has recently emerged in asthma concerns the role of the bronchial epithelium as a key regulator of airway inflammatory and remodelling responses in asthma. It has been shown by our group that the disruption and alteration in the function of the lower airway epithelium in asthma leads to the generation of a variety of stimuli that lead to the restructuring of the airway wall. This raises interesting questions regarding a similar role for the upper airway epithelium in allergic rhinitis. This review aims to interpret past and current research into allergic rhinitis, and to address specific areas where future research is warranted, particularly in relation to the possibility of an altered upper airway epithelial phenotype in allergic rhinitis.

Asthma↗

PubMed2003

Remodelling of the upper airways in allergic rhinitis: is it a feature of the disease?

The traditional viewpoint that inflammation, owing to a genetic T-helper type 2 (Th2)-directed imbalance, is the cause of allergic rhinitis has meant that the potential coexistence of other genetic defects and the relevance of any airway remodelling changes to disease pathogenesis and persistence have received scant attention, and as such remain controversial areas. This is particularly so in view of the limited published work in this field, which has so far reported markedly conflicting findings. This review endeavours to outline what is known about the nature of the remodelling response within the upper airway in allergic rhinitis, in addition to highlighting specific areas where further research is warranted.

Capillary Permeability↗

PubMed2003

Pharmacotherapy and airway remodelling in asthma?

Over the last few decades attention has largely focused on airway inflammation in asthma, but more recently it has been appreciated that there are important structural airway changes which have been grouped together under the term "airway remodelling". It is only now that questions have been asked about the impact of treatment on these structural changes. This review examines the nature of these structural airway changes, the mechanisms of their generation, their potential consequences, and what is known about the ability of anti-asthma treatments to modulate these changes.

Adrenal Cortex Hormones↗

PubMed2001

Basic fibroblast growth factor in asthma: measurement in bronchoalveolar lavage fluid basally and following allergen challenge.

Airway remodeling in asthma refers to a collection of chronic structural changes including subepithelial fibrosis, airway smooth muscle hypertrophy/hyperplasia, and possibly angiogenesis. The mechanisms leading to remodeling are not well defined. One molecule of possible relevance is basic fibroblast growth factor (bFGF), which is a potent mitogen for fibro-blasts, airway smooth muscle cells, and endothelial cells. To test the hypothesis that bFGF expression is increased in asthma, we measured levels of the growth factor in bronchoalveolar lavage (BAL) fluid. Basally, BAL fluid bFGF concentrations were significantly higher in subjects with atopic asthma than in control subjects without asthma (median 0.22 vs 0.06 pg/mL, P = .003). The effect of acute allergen exposure was examined with a segmental bronchoprovocation model in a separate group of subjects with atopic asthma. Ten minutes after segmental bronchoprovocation there was a 5-fold increase in bFGF levels in BAL fluid recovered from allergen-challenged sites compared with control saline-challenged sites (1.52 vs 0.30 pg/mL, P < .002). We conclude that basal levels of BAL fluid bFGF are increased in atopic asthma and that a further increase occurs in response to acute allergen exposure. These findings lend support to the hypothesis that bFGF is implicated in airway remodeling in asthma.

Adult↗

PubMed2001

Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium.

BACKGROUND: Asthma is associated with increased production of IL-4 and IL-13. OBJECTIVE: Because many of the effects of these cytokines are mediated by activation of signal transducer and activator of transcription 6 (STAT-6), we investigated expression and function of this transcription factor in the airways. METHODS: STAT-6 expression was investigated through use of immunohistochemistry or RT-PCR applied to bronchial biopsy specimens or brushings from normal control or asthmatic subjects. STAT-6 function was investigated by means of Western blotting and ELISA applied to primary epithelial cell cultures. RESULTS: Immunohistochemistry revealed that the bronchial epithelium was the major site of STAT-6 expression, both cytoplasmic and nuclear staining being observed. The level of STAT-6 expression in subjects with mild asthma (median [range] percent epithelial staining, 3.4% [0% to 16.0%]; n = 14) did not differ significantly from that in normal controls (4.7% [0.0% to 20.0%]; n = 11); however, in subjects with severe asthma, epithelial STAT-6 expression (13.7% [4.8% to 25.7%]; n = 9) was increased in comparison with subjects with mild asthma and normal controls (P < .05). RT-PCR analysis showed that epithelial STAT-6 expression was heterogeneous and comprised both full-length STAT-6 and the dominant-negative variant that lacks the SH2 domain. Treatment of primary cultures of bronchial epithelial cells with IL-4 resulted in STAT-6 phosphorylation and stimulation of IL-8 secretion; however, no difference in the responses of epithelial cells was observed between normal (n = 12) and asthmatic (n = 14) donors. CONCLUSION: These data demonstrate expression and activation of STAT-6 in normal and asthmatic bronchial epithelium. The activity of this transcription factor is likely to play a key role in mediating the responses of the bronchial epithelium to T(H)2 cytokines that are characteristic of the asthmatic phenotype.

Asthma↗

PubMed2001

Why particle size should affect clinical response to inhaled therapy.

Studies with beta2-adrenergic agonists have shown that particle size and total dose are important determinants of optimum bronchodilation. Drug deposition in the airways is probably the most important factor for bronchodilation, since beta2-adrenoceptors and muscarinic M3 receptors are present mainly in the peripheral and central airways, respectively. Furthermore, clinical efficacy can be maintained while minimizing systemic exposure by selecting an appropriate particle size. Changes in lung function provide a means of monitoring the relationship between delivery of the bronchodilator and its efficacy, whereas there is no such immediate means of assessing antiinflammatory preventative therapy such as inhaled corticosteroids. Asthma is primarily an inflammatory disease but there are no simple tests to detect the accumulation of inflammatory cells and mediators. Data are presented to demonstrate the reduction of certain inflammatory markers in bronchial biopsy tissue taken from asthmatic patients after corticosteroid therapy. Measurement of inflammatory markers in both bronchial biopsy tissue and bronchoalveolar lavage samples may provide a way of monitoring the site of action and efficacy of inhaled corticosteroids in the future. Furthermore, it is envisaged that the effect of corticosteroid particle size on efficacy and systemic bioavailability may be investigated by exploiting these methods.

Administration, Inhalation↗

PubMed2001

Increased expression of inducible nitric oxide synthase and cyclo-oxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment.

BACKGROUND: Nitric oxide (NO) and prostanoids are mediators of vascular and bronchial tone that are postulated to be involved in asthma. Increased levels of both are found in asthmatic subjects and are synthesised by enzymes that have cytokine inducible forms: inducible NO synthase (iNOS) and cyclo-oxygenase-2 (COX-2), respectively. We hypothesised that the in vivo expression of iNOS and COX-2 in the airways would be increased in asthma, and that these cytokine inducible enzymes may represent targets for regulation by corticosteroid treatment. METHODS: Bronchial biopsy specimens were obtained from three groups of subjects: atopic asthmatics treated with beta(2) agonists alone (n=7), atopic asthmatics additionally receiving regular treatment with corticosteroids (n=8), and non-asthmatic control subjects (n=10). Expression of iNOS and COX-2 mRNA and immunoreactive protein was studied using in situ hybridisation and quantitative immunohistochemistry. RESULTS: Immunoreactivity and the hybridisation signal for iNOS and COX-2 were mainly localised in the airway epithelium. The proportion of epithelium immunostained was significantly greater in the non-steroid treated asthmatic subjects (iNOS 8.6 (1.8)%; COX-2 26.3 (4.6)%) than either the steroid treated asthmatics (iNOS 3.4 (1.0)%, p=0.009; COX-2 13.0 (0.6)%, p=0.0015) or the non-asthmatic controls (iNOS 4.2 (0.9)%, p=0.018; COX-2 11.6 (0.6)%, p=0.0003). Similarly, the hybridisation signal was stronger in the non-steroid treated group of asthmatic subjects than in the other two groups. CONCLUSIONS: These findings highlight the potential role of the airway epithelium both as a contributor to the inflammatory process in asthma and as a target for inhaled corticosteroid treatment in this disease.

Adrenal Cortex Hormones↗

PubMed2001

The relationship between atopic status and IL-10 nasal lavage levels in the acute and persistent inflammatory response to upper respiratory tract infection.

We examined the influence of atopy on virus-induced airway inflammation by comparing the nasal response to naturally acquired upper respiratory tract infection in atopic and nonatopic subjects by measurement of cytokine, chemokine, and mediator levels in nasal lavage from 44 adults (23 atopic) taken during the acute and the convalescent phases of the common cold. Nasal aspirates were examined for the presence of upper respiratory viruses by RT-PCR. In atopic and nonatopic subjects there were increased levels of IL-1beta, IL-6, IL-8, TNF-alpha, RANTES, sICAM-1, MPO, ECP, IL-10, and IFN-gamma in nasal lavage during the acute compared with the convalescent phase (p < 0.001). During the acute phase histamine levels were significantly higher in the atopic than in the nonatopic subjects (p < 0.05), whereas IL-10 levels were significantly greater in the nonatopic than in the atopic subjects (p < 0.05). At convalescence levels of IL-1beta, IL-6, sICAM-1, ECP, RANTES and albumin were significantly higher in the atopic group (p < 0.05). An upper respiratory tract virus was found in 27 volunteers (61%) during the acute stage and in two volunteers (4%) at convalescence. We conclude that virus-induced inflammatory changes within the nose are more prolonged in atopic than in nonatopic subjects and that this is associated with reduced IL-10 levels in atopic compared with nonatopic subjects during the acute phase of upper respiratory tract infection.

Acute-Phase Proteins↗

PubMed2001

Exhaled nitric oxide levels in exacerbations of asthma, chronic obstructive pulmonary disease and pneumonia.

OBJECTIVE: Nitric oxide is known to be present in the exhaled air of normal subjects and at higher concentrations in asthmatics. The aim of this study was to measure exhaled nitric oxide levels in patients admitted to hospital with acute exacerbations of asthma, or chronic obstructive pulmonary disease, or with pneumonia. METHODS: Within 24 hours of admission exhaled nitric oxide levels were measured by a chemiluminescent analyzer in 11 patients with acute sever asthma, 19 patients with acute exacerbation of chronic obstructive pulmonary disease, and in 12 patients with pneumonia. In asthmatics measurements were made on 3 occasions, at day 1, 4, and 28 and were related to changes in peak expiratory flow rate. RESULTS: On admission median exhaled nitric oxide levels (range) were significantly higher in asthmatics 22 (9.3-74) parts per billion in comparison to patients with chronic obstructive pulmonary disease 10.3 (2.7-34) parts per billion; p < 0.01, pneumonia 7 (4-17) parts per billion; p<0.001, and normal subjects 8.7 (5-13.3) parts per billion; p < 0.001. Following treatment the asthmatics had a significant reduction in their exhaled nitric oxide levels from 22 (9.3-74) parts per billion on day 1 to 9.7 (5.7-18.3) parts per billion on day 28; p = 0.005. Peak expiratory flow rate measurements increased from 200 (120-280) l/min on day 1 to 280 (150-475) l/min on day 4; p < 0.05 and to 390 (150-530) l/min on day 28; p < 0.01. A strong negative correlation existed between peak expiratory flow rate measurements and exhaled nitric oxide levels in asthmatics on day 28 (r = -0.70; p = 0.017). CONCLUSION: Acute exacerbations of asthma are associated with increased levels of exhaled nitric oxide in contrast to exacerbations of chronic obstructive pulmonary disease and acute pneumonia. Exhaled nitric oxide may be a useful indirect marker of asthmatic airway inflammation. The differing time course of response of nitric oxide to peak flow measures suggests that these two measures are reflecting differing airway events.

Adolescent↗

PubMed2000

Validation of endobronchial biopsy specimens for nerve quantitation by computer-assisted image analysis.

The aim of this study was to assess the validity of endoscopic bronchial biopsy specimens for the quantitation of nerves. To this end, endobronchial biopsy was simulated ex vivo on surgically resected lung specimens and nerve densities were compared in airway smooth muscle of biopsy and surrounding tissue. Specimens were stained immunohistochemically for the general neural marker protein gene product 9.5 (PGP 9.5) and for vasoactive intestinal peptide (VIP), and nerve densities were quantitated using computer-assisted image analysis. Nerve density for total (PGP 9.5-immunoreactive) nerves was slightly higher in biopsies than in corresponding lung tissue, but this difference did not reach statistical significance (p=0.08). There was also no significant difference in the density of VIP-immunoreactive nerves (p=0.60). These findings support the use of endobronchial biopsy specimens to quantitate nerves in asthma and other airway diseases.

Biomarkers↗

PubMed2000

The effect of long-acting beta2-agonists on airway inflammation in asthmatic patients.

Early observations suggested that the inhibition by long-acting beta2-agonists (LABAs) of non-specific bronchial hyperresponsiveness following allergen challenge was unrelated to bronchodilation or functional antagonism and might be a reflection of anti-inflammatory activity. Investigation of the effect of LABAs on airway inflammatory responses has demonstrated an inhibition of eosinophil recruitment in allergen challenge studies. Nevertheless, results from biopsy and other studies suggest that the chronic inflammatory process in asthma patients is unaffected by these drugs. There is no evidence from biopsy studies that LABAs are pro-inflammatory or that they mask existing inflammation. The beneficial effects of LABAs in allergen challenge are probably mediated through stabilization of mast cells. Recent evidence suggests that LABAs may reduce numbers of neutrophils and their associated markers; this observation needs to be confirmed in future studies and its relevance to the treatment of asthma determined.

Adrenergic beta-Agonists↗

PubMed2000

Persistent airway T-lymphocyte activation in chronic corticosteroid-treated symptomatic asthma.

BACKGROUND: A small proportion of patients with asthma have persistent symptoms despite regular treatment with high-dose inhaled and/or oral corticosteroids. There is little information regarding immunopathology in such patients. OBJECTIVE: To compare airway inflammatory changes in subjects with chronic corticosteroid-dependent symptomatic asthma (n = 5) and subjects with asthma that was clinically well controlled on inhaled corticosteroid therapy (n = 9). Subjects in the corticosteroid-dependent group were receiving long-term treatment with oral prednisolone and high-dose inhaled corticosteroids. METHODS: Subjects underwent fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy. T-lymphocytes subsets and activation markers in BAL fluid and peripheral blood were determined by FACS analysis. Bronchial biopsies were stained immunohistochemically, and numbers of inflammatory cells quantitated. Inflammatory mediators in BAL fluid were measured by immunoassay. RESULTS: There was significantly greater expression of CD25 (P = .02) and HLA-DR (P = .04) by BAL fluid T-lymphocytes in corticosteroid-treated symptomatic asthmatics. In bronchial biopsies there were no significant differences between the two groups in the numbers of AA1+ cells (mast cells), EG2+ cells (eosinophils) or MT1+ T-lymphocytes. Levels of albumin, histamine, tryptase, and eosinophil cationic protein in BAL fluid did not differ significantly between groups. CONCLUSIONS: Chronic corticosteroid-treated symptomatic asthma is associated with persistent airway T-lymphocyte activation. This, however, is not necessarily accompanied by the recruitment and activation of inflammatory cells within the airways.

Administration, Inhalation↗