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Biomedical subjects

Ron Olivenstein

Publications and source records attributed to Ron Olivenstein.

8 recordsLinked to original sources
PubMed2006

Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes.

BACKGROUND: Airway inflammation assessed by bronchial biopsies demonstrates distinct eosinophilic and noneosinophilic phenotypes in severe asthma, but their relationship to other biomarkers of disease (induced sputum and nitric oxide [NO]) is not clear. OBJECTIVES: We sought to compare airway inflammation using noninvasive (induced sputum, exhaled NO), and invasive (bronchial biopsies) methods in moderate and severe asthma and to assess whether induced sputum and exhaled NO would allow the identification of eosinophilic and noneosinophilic phenotypes in severe asthma. METHODS: We performed a cross-sectional study of 32 subjects with severe asthma and 35 subjects with moderate asthma, from whom we obtained bronchial biopsies, induced sputum, and exhaled NO measurements. RESULTS: Among subjects with severe asthma, we identified eosinophilic and noneosinophilic phenotypes using both bronchial biopsies and sputum cell counts. However, the vast majority of subjects with high sputum eosinophil counts did not have high mucosal eosinophil counts. Exhaled NO was increased in the eosinophilic phenotype as judged from bronchial biopsy findings, but not on the basis of induced sputum. Subjects with high sputum eosinophil counts experienced more asthma exacerbations than the subjects with low sputum eosinophil counts. In contrast, we did not find any differences in the clinical characteristics between eosinophilic and noneosinophilic phenotypes that were identified by bronchial biopsies. CONCLUSION: The use of sputum cell counts allowed the identification of a subgroup of subjects with severe asthma who were at risk of more frequent asthma exacerbations. CLINICAL IMPLICATIONS: Monitoring sputum eosinophil counts in subjects with severe asthma may allow identifying the subjects with the greatest disease activity.

Asthma↗
PubMed2006

Effects of hydrofluoroalkane and dry powder-formulated corticosteroids on sputum inflammatory markers in asthmatic patients.

BACKGROUND: Inhaled corticosteroids are powerful drugs that can suppress airway inflammation in asthmatic patients. Deposition of most of the inhaled corticosteroid occurs mainly in the central airways. However, a new hydrofluoroalkane formulation of beclomethasone dipropionate (HFA-BDP) is preferentially deposited in the distal airways. Inflammatory characteristics of induced sputum have been shown to differ in samples collected early after sputum induction compared with later. OBJECTIVE: To compare the effects of HFA-BDP and budesonide in a dry powder inhaler (DPI-BUD) on inflammatory cells and inflammatory cytokine expression in early and late induced sputa compared with placebo. METHODS: Seventeen patients with mild, intermittent bronchial asthma were randomly assigned to two treatment groups: eight patients received HFA-BDP and nine patients received DPI-BUD. Each patient was treated with one of the active treatments and placebo (for four weeks), with a two-week washout interval in between. Inflammatory cells and expression of interleukin (IL)-4 and IL-5 were measured in early and late induced sputa before and after active treatment, as well as before and after placebo treatment using immunocytochemistry and in situ hybridization. RESULTS: Compared with placebo, eosinophils were significantly reduced in both early and late induced sputa after HFA-BDP treatment (P<0.05), whereas DPI-BUD had a significant effect only on early induced sputum. Both HFA-BDP and DPI-BUD decreased IL-4 expression in early and late induced sputa, but the effect was more prominent with HFA-BDP. IL-5 expression was reduced in both early and late induced sputa after HFA-BDP treatment. DPI-BUD significantly decreased IL-5 expression in early but not in late induced sputum. The number of lymphocytes was not altered by either treatment. CONCLUSIONS: HFA-BDP reduced eosinophilic inflammation and T helper 2-type cytokine expression in both early and late induced sputa, whereas the effect of DPI-BUD on inflammation was predominantly demonstrated in early induced sputum.

Administration, Inhalation↗
PubMed2005

Differences in airway remodeling between subjects with severe and moderate asthma.

BACKGROUND: Airway remodeling in asthma comprises a range of structural changes. Several studies have suggested an association between these changes and disease severity. The relationship between the extent of remodeling and lung function is not well defined. OBJECTIVE: We sought to contrast the structural changes in the airways of well-defined groups of subjects with severe and moderate asthma and to correlate the extent of remodeling with disease severity. METHODS: Endobronchial biopsy specimens were obtained from 15 subjects with severe and 13 subjects with moderate asthma. Epithelial integrity, cell-layer areas, subepithelial fibrosis, and the distance between epithelial and airway smooth muscle (ASM) layers were measured by means of image analysis. Collagen was identified by using Van Giesen stain, and ASM was defined by using smooth muscle alpha-actin immunostaining. Specific immunostains were performed for the evaluation of RANTES, IL-8, and eotaxin expression as markers of ASM phenotype. RESULTS: ASM area was greater in subjects with severe (0.24+/- 0.03 mm(2)) than in subjects with moderate (0.05+/- 0.01 mm(2)) asthma (P<.001). The distance between the epithelial and ASM layers was less in the severe group (0.12+/- 0.01 mm) than in the moderate group (0.24+/- 0.02, P<.001). A trend toward greater subepithelial fibrosis in subjects with severe asthma did not reach statistical significance. IL-8 and eotaxin expression, but not RANTES expression, were increased in the ASM of subjects with severe asthma compared with in subjects with moderate asthma. CONCLUSION: Smooth muscle alteration is the key structural change that distinguishes severe from moderate asthma, and phenotypic change in ASM might contribute to the difficulty in obtaining adequate control in some subjects with severe asthma.

Adult↗
PubMed2005

Increased expression of the calcium-activated chloride channel hCLCA1 in airways of patients with obstructive chronic bronchitis.

BACKGROUND: Interleukin (IL)-9 and its effect on enhancing the human calcium-activated chloride channel 1 (hCLCA1) expression have been shown to induce mucin production. Increased expression of hCLCA1 may, in turn, contribute to mucus overproduction in chronic obstructive pulmonary disease (COPD) with a chronic bronchitis (CB) phenotype. OBJECTIVE: To determine the expression of IL-9, IL-9 receptor (IL-9R), hCLCA1 and mucoglycoconjugates in COPD. METHODS: Bronchial biopsies were obtained from six patients with obstructive CB and six healthy control subjects. IL-9, IL-9R and hCLCA1 expression were detected using immunohistochemistry. Additionally, in situ hybridization was performed to determine the expression of hCLCA1 messenger RNA. Mucin production was assessed using periodic acid-Schiff staining. RESULTS: There was a significantly higher number of IL-9 immunoreactive cells in the submucosa of patients with COPD than that of healthy control subjects (P<0.05). Also, a significant increase in the expression of IL-9R, hCLCA1 (protein and messenger RNA) and mucin (periodic acid-Schiff-positive cells) was noted in the bronchial epithelium of patients with COPD compared the control subjects (P<0.05). CONCLUSION: Increased expression of IL-9, IL-9R and hCLCA1 in the bronchial mucosa of patients with obstructive CB suggests that mucus overproduction in this disease may be, at least in part, due to hCLCA1.

Aged↗
PubMed2004

Fractional analysis of Th2-type cytokines in sequential samples of induced sputum.

BACKGROUND: Recent studies have demonstrated the usefulness of induced sputum in detecting the expression of Th2-type cytokines in asthmatics and have shown that the profile of inflammatory cells in induced sputum differs with time. OBJECTIVE: To determine whether the duration of sputum induction also affects the expression of Th2-type cytokines in induced sputum. METHODS: Induced sputum was collected from eight atopic asthmatics at two separated intervals (5 min each) during a 15 min sputum induction, and each sample was examined separately for cytokine expression and inflammatory cells. Using immunocytochemistry, interleukin (IL)-4 and IL-5 immunoreactivity, T lymphocytes (CD3), eosinophils (major basic protein), neutrophils (elastase), epithelial cells and macrophages (CD68) were compared in the induced sputum obtained from the 0 min to 5 min and the 10 min to 15 min samples. RESULTS: The number of immunoreactive-positive cells expressing IL-4 and IL-5 were significantly higher in the 10 to 15 min induced sputum sample than in the 0 min to 5 min induced sputum sample (P<0.05). The number of eosinophils was also significantly higher in the 10 min to 15 min sample than in the 0 min to 5 min sample (P<0.05). In contrast, the number of neutrophils was significantly higher in the 0 min to 5 min sample than in the 10 min to 15 min sample (P<0.01); T lymphocytes, macrophages and epithelial cells did not differ between the two samples. CONCLUSION: This study demonstrates that the duration of sputum induction significantly affects the profile of inflammatory cells and Th2-type cytokine expression, and underscores the need for the standardization of induced sputum procedure.

Adult↗
PubMed2003

T helper type 2 cytokine receptors and associated transcription factors GATA-3, c-MAF, and signal transducer and activator of transcription factor-6 in induced sputum of atopic asthmatic patients.

BACKGROUND: It is well-known that the expression of T helper (Th) type 2 cytokines such as interleukin (IL)-4 and IL-5, and their receptors, is up-regulated within the airways of allergic asthmatic patients. Furthermore, higher numbers of cells producing GATA-3, c-MAF, and signal transducer and activator of transcription factor (STAT)-6, which are transcription factors (TFs) that are implicated in the regulation and signaling of the Th2 cytokines, have been observed in bronchial biopsy specimens from asthmatic patients but not in those of healthy control subjects. METHODS: We examined whether these mediators also can be detected in induced sputum. Immunoreactivity for IL-4Ralpha, IL-5Ralpha, GATA-3, c-MAF, and STAT-6 was investigated in samples of induced sputum from asthmatic patients (n = 8) and healthy control subjects (n = 8). RESULTS: Our results showed that the numbers of cells expressing IL-4 receptor alpha (Ralpha) and IL-5Ralpha were higher in samples from asthmatic patients compared to those of control subjects (p < 0.01). More cells exhibiting GATA-3, c-MAF, and STAT-6 immunoreactivity also were found in asthmatic patients vs those in control subjects (p < 0.005). Furthermore, the expression of STAT-6 and IL-4Ralpha, GATA-3 and IL-5Ralpha, and c-MAF with both IL-4Ralpha and IL-5Ralpha was correlated (p < 0.05). CONCLUSIONS: This study demonstrated that induced sputum provides sufficient sensitivity for examining the pathways of cytokine signaling, cytokine receptor signaling, and intracellular signaling. Furthermore, these data show correlations between the expression of Th2 cytokine receptors and associated TFs in the human lung, which has not been documented previously.

Adult↗
PubMedDate not supplied

Toll-like receptors 4 and 2 expression in the bronchial mucosa of patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a lung disease characterized by chronic infection with Gram-negative bacteria Pseudomonas aeruginosa and Gram-positive bacteria Staphylococcus aureus. Recently, toll-like receptor (TLR) 4 has been shown to be responsible for the lipopolysaccharide (LPS)-mediated immune response. While TLR2 mediates responses driven by bacterial lipoproteins and peptidoglycans from Gram-positive bacteria, LPS derived from P aeruginosa may stimulate the immune response in the airways of patients with CF via activation of TLR4. OBJECTIVES: To investigate TLR4 and TLR2 expression in the bronchial mucosa of patients with CF and normal control subjects. PATIENTS AND METHODS: Endoscopic bronchial biopsies from seven patients with CF and six healthy control subjects were obtained. TLR4 and TLR2 expression was assessed using immmunocytochemistry. Real-time polymerase chain reaction was used to detect TLR4 messenger RNA in blood cells from patients with CF and to compare TLR4 expression in CF bronchial epithelial cells with non-CF bronchial epithelial cells. RESULTS: In patients with CF, the number of TLR4-positive cells was significantly increased in their submucosa (P<0.05) but significantly reduced in their epithelium compared with control subjects (P<0.05). The majority of TLR4-positive cells were neutrophils. Patients with CF (n=4) and control subjects (n=4) had a similar percentage of TLR4-expressing neutrophils and monocytes/lymphocytes in peripheral blood. CF cells (IB-3) had significantly decreased basal TLR4 messenger RNA expression compared with non-CF cells (Calu-3) (P<0.05). Although there was a trend toward reduced TLR2 expression in the airway epithelium of patients with CF (P=0.07), there was no significant difference in TLR2 expression in the submucosa of patients with CF compared with that of control subjects. CONCLUSIONS: Both TLR4 and TLR2 expression in the bronchial epithelium of patients with CF were significantly reduced compared with healthy control subjects. In contrast, the number of TLR4-positive neutrophils in the submucosa of patients with CF was higher than in control subjects. This may suggest that the loss of epithelial TLR expression may contribute to the impaired defense against LPS.

Adult↗