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Biomedical subjects

I Vachier

Publications and source records attributed to I Vachier.

At least 19 recordsLinked to original sources
PubMed2004

Inflammatory features of nasal mucosa in smokers with and without COPD.

BACKGROUND: To investigate whether nasal and bronchial inflammation coexists in chronic obstructive pulmonary disease (COPD), nasal and bronchial biopsy specimens from seven control subjects, seven smokers without COPD, and 14 smokers with COPD were studied. METHODS: Nasal and bronchial biopsy specimens were taken from the same patients during bronchoscopy and squamous cell metaplasia and the thickness of the epithelium and basement membrane were measured. The numbers of eosinophils (EG2), neutrophils (elastase), macrophages (CD68), and CD8 T lymphocytes (CD8/144B) were assessed by immunohistochemistry. RESULTS: Smokers with and without COPD had squamous metaplasia in the nasal and bronchial epithelium. In all groups the thickness of the nasal epithelium was greater than that of the bronchial epithelium. The thickness of the basement membrane was similar in nasal and bronchial biopsy specimens from smokers with and without COPD, but was greater in the bronchi than in the nasal epithelium of controls. Eosinophil number was higher in the nasal and bronchial mucosa of smokers without COPD than in smokers with COPD or controls. Neutrophil number was higher in the nasal and bronchial mucosa of smokers with COPD than in smokers without COPD or controls. CD8 T lymphocyte numbers were similar in smokers with and without COPD and higher than in controls. There were fewer macrophages in nasal and bronchial biopsy specimens from smokers without COPD than in those with COPD. CONCLUSION: Nasal and bronchial inflammation coexists in smokers and is characterised by infiltration of CD8 T lymphocytes. In smokers without COPD this feature is associated with an increased number of eosinophils, while in those with COPD it is linked to an increased number of neutrophils in both nasal and bronchial biopsy specimens.

Adult↗
PubMed2003

Glucocorticoid receptor-binding characteristics in severe asthma.

The cellular mechanisms associated with severe asthma are still poorly understood. This study investigated the association between glucocorticoid-receptor (GR) alterations and continuous oral glucocorticoid therapy requirement in severe asthma. GR-binding affinity (Kd) and receptor number (n) in peripheral blood monocytes (PBM) obtained from 10 normal subjects, 10 untreated, intermittent asthmatics and 10 severe asthmatics were assessed. Moreover, one ability of dexamethasone to inhibit regulated on activation, T-cells expressed and secreted (RANTES) release by these cells in vitro was investigated. GR-binding characteristics were studied in PBM using a 3H dexamethasone ligand-binding assay and Scatchard analysis. RANTES release was measured in the supernatant of PBM at 24 h using an enzyme-linked immunosorbent assay. No significant differences in Kd and n were found between the three groups of patients. Dexamethasone in vitro was able to inhibit RANTES release (mean+/-SEM), with the same concentration/response curve in intermittent, untreated asthmatics (0.47+/-0.22 versus 1.64+/-0.31 ng x mL(-1)) and severe asthmatics (1.49+/-0.64 versus 2.59+/-0.77 ng x mL(-1)). This study showed that, despite long-term treatment with oral glucocorticoids, there was no evidence of abnormalities in glucocorticoid receptor-binding characteristics in severe asthma, and moreover, it was demonstrated that glucocorticoid receptors were functional in vitro.

Administration, Oral↗
PubMed2002

Endogenous anti-inflammatory mediators from arachidonate in human neutrophils.

Eicosanoids have been historically involved in the pathogenesis of various inflammatory diseases. Lipoxins (LXs) and epi-LXs show physiological effects relevant to inflammation regulation. In this study, we focused on LX precursors based on the hypothesis that their entrance and metabolism into the cell may facilitate their targeting at the inflammation site. Because compound chirality is of considerable importance in the efficacy of therapeutic agents, our aim was to study the anti-inflammatory effects of various epimers of LXA(4) precursors compared to LXA(4). Blood polymorphonuclear cells (PMNs) were incubated with 15(S)- or 15(R)-hydroxyeicosatetraenoic acid (HETE), 14(R)-,15(S)-, or 14(S),15(S)-diHETE, and LXA(4) and then stimulated with the calcium ionophore A23187. We found that 15(R)-HETE rather than 15(S)-HETE was preferentially metabolized and that 15-epi-LXs were produced in larger amounts than LXs. In contrast, when PMNs were incubated with the diastereoisomers of 14,15(S)-diHETE, 14-epi-LXB(4) was produced in lower amounts than LXB(4). Enantiomers of 15-HETE and diastereoisomers of 14,15-diHETE and LXA(4) were able to significantly decrease LTB(4) release by PMNs. These results suggest a potential resolution of the inflammatory process through endogenous anti-inflammatory mediators released by the way of trans-cellular metabolism.

Anti-Inflammatory Agents↗
PubMed2002

Regulation of E-cadherin expression by dexamethasone and tumour necrosis factor-alpha in nasal epithelium.

Asthma and rhinitis often coexist and share many clinical features. The extent of epithelial alteration in nasal inflammation is controversial. Cell-cell adhesion plays an important role in tissue morphogenesis and homeostasis and is mediated by the cadherin family. In human bronchial epithelial cells the authors have shown that tumour necrosis factor (TNF)-alpha induced a significant decrease of E-cadherin and beta-catenin expression. The addition of dexamethasone inhibited this decrease. The aim of the present study was to investigate the effect of TNF-alpha and dexamethasone on the regulation of E-cadherin, gamma-catenin and beta-catenin in human nasal epithelial cells (HNEC). A primary culture of HNEC, obtained from human nasal turbinates after surgery, was used. The quantitative and qualitative modulation of E-cadherin, gamma-catenin and beta-catenin expression was assessed by Western blot and immunofluorescence analysis. In order to assess the TNF-alpha-induced activation of HNEC, interleukin-8 and RANTES (regulated on activation, normal T-cell expressed and secreted) release was assessed by enzyme-linked immunosorbent assay. The results showed that TNF-alpha induced, a decrease in gamma-catenin and beta-catenin expression, but had no effect on E-cadherin expression. Immunofluorescence showed that TNF-alpha induced cytoplasmic localisation of E-cadherin, gamma-catenin and beta-catenin. Dexamethasone inhibited the effect of TNF-alpha and induced a three-fold increase in E-cadherin expression. These results suggest that the difference in nasal and bronchial epithelial cohesion may be due to the differential effect of tumour necrosis factor-alpha and dexamethasone on E-cadherin expression.

Blotting, Western↗
PubMed2002

Eosinophilic inflammation in sputum of poorly controlled asthmatics.

Despite full effective treatment, asthmatic patients often present with poorly controlled asthma. Airway eosinophilia is associated with asthma, but its relationship with asthma control is still undetermined. To investigate the relationship between airway eosinophilia and asthma control, cellular and biochemical markers of airway inflammation were measured in 19 subjects with poorly controlled asthma, 16 subjects with asthma under control and eight normal volunteers. The severity of asthma was mild-to-moderate persistent in 23 patients (14 poorly controlled) and severe prednisone-dependent in 12 subjects (five poorly controlled). Induced sputum was analysed for total and differential cell counts, leukotriene E4 (LTE4), eosinophil cationic protein (ECP), regulated on activation, normal T-cell expressed and secreted (RANTES), and interleukin (IL)-8. Sputum eosinophils, LTE4, ECP and RANTES levels (but not IL-8) were significantly higher in patients with poorly controlled asthma as compared to patients with controlled asthma. By contrast, sputum cells and sputum inflammatory markers were not different among groups of patients with different severity of asthma. These results suggest that sputum eosinophilia is associated with poorly controlled asthma rather than with the severity of asthma.

Adult↗
PubMed2001

Disease activated drugs: a new concept for the treatment of asthma.

Disease activated drugs (DAD) are pro-drugs of one active principle or combinations of two drugs, which have a proven efficacy for the treatment of the target disease. In opposition to pro-drugs, DAD are activated in inflamed but not normal tissues. Due to the disease specific activation, the amount of locally released drug(s) should be related directly to the severity of the inflammation. To test this concept in asthma a PDE4 inhibitor, an isoquinoline derivative, was chemically derivatized into pro-drugs or combined with corticosteroids. These new compounds were more readily cleaved into active PDE4 inhibitor, in bronchoalveolar lavage fluid (BALF) from Brown-Norway rats with lung inflammation than in BALF from rats without airway inflammation. The DAD concept (local selective release and improved therapeutic window) was validated in vivo using the inhibition of methacholine induced bronchoconstriction in guinea pigs with or without ozone induced lung inflammation. An example of DAD hydrolysis (isoquinoline-dexamethasone) was also examined in BALF from asthmatics and healthy volunteers.

Animals↗
PubMed2001

Sputum eosinophilia in Churg-Strauss syndrome.

Sputum induction (IS) can be used to study airway inflammation in asthmatics and other lung diseases. However, no data are available for patients with Churg-Strauss syndrome (CSS). A study was carried out to evaluate eosinophil counts and eosinophil cationic protein (ECP) levels in induced sputum during the follow-up of three patients with CSS. Induced sputum was carried out in 10 patients with corticosteroid-dependent asthma (used as a control group). Patients with CSS had significantly higher eosinophils percentages and ECP levels in sputum than those with stable corticosteroid-dependent asthma. During the follow-up, patients with CSS presented increased ECP levels sputum and eosinophils in sputum as well as increased blood eosinophils, despite their oral corticosteroid and immunosuppressive treatment. Eosinophil percentage in sputum and the total number of eosinophils in peripheral blood were more predictive of exacerbations of CSS than sputum ECP.

Acute Disease↗
PubMed2001

Rhinosinusitis in severe asthma.

BACKGROUND: Chronic rhinosinusitis is a common comorbidity of asthma. However, sinonasal involvement in severe steroid-dependent asthma is still undefined. OBJECTIVE: The aim of the study was to evaluate chronic rhinosinusitis in 35 patients with severe steroid-dependent asthma by using a clinical score and coronal computed tomography (CT) scanning. METHODS: Thirty-five subjects (16 female subjects) with severe asthma requiring daily doses of oral corticosteroids were compared with 34 patients (19 female patients) with mild-to-moderate asthma. Sinonasal involvement was studied by using clinical and CT scores. Airflow obstruction, therapy requirement, and asthma triggering factors were carefully assessed. RESULTS: The proportion of patients with symptoms of rhinosinusitis was similar in both groups of asthmatic subjects (74% in patients with severe steroid-dependent asthma and 70% in patients with mild-to-moderate asthma). All subjects with steroid-dependent asthma versus 88% of subjects with mild-to-moderate asthma had abnormal CT scan results. The clinical (P <.05) and CT scan (P <.0005) severity scores were higher in the subjects with severe steroid-dependent asthma. In both groups the CT scan scores were correlated to the clinical scores (P <.0001 and P <.006), but only in the mild-to-moderate group were both scores correlated with high significance (P <.002 and P <.0005) to the absolute number of blood eosinophils. CONCLUSION: Frequency of rhinosinusitis in patients with mild-to-moderate or severe steroid-dependent asthma is similar; however, sinonasal involvement, as evaluated by clinical symptoms and CT scan imaging, is significantly greater in the patients with severe steroid-dependent asthma than in those with mild-to-moderate asthma.

Adolescent↗
PubMed2001

Effects of glucocorticoids on endogenous and transcellular metabolism of eicosanoids in asthma.

BACKGROUND: Human blood polymorphonuclear cells, which biosynthesize eicosanoids from the 5-lipoxygenase (5-LO) pathway, are likely to be involved in asthma, in which glucocorticoids represent the first line of therapy. Their effects on leukotriene release after a short course of treatment, which have been reported in several studies, are controversial. OBJECTIVE: We sought to investigate whether long-term oral glucocorticoids inhibit lipid mediators from the 5-LO pathway. METHODS: Twelve normal control subjects, 29 asthmatic subjects, and 50 glucocorticoid-dependent asthmatic subjects were included in the study. Polymorphonuclear cells were studied for endogenous and transcellular metabolism of eicosanoids. RESULTS: Total leukotriene B(4) production was significantly lower in cells from glucocorticoid-dependent asthmatic subjects (mean +/- SD, 177 +/- 26 ng/10(7) cells) than in control subjects (406 +/- 27), untreated asthmatic subjects (421 +/- 34), and asthmatic subjects treated with inhaled glucocorticoids (290 +/- 56). When incubated with arachidonic acid, these polymorphonuclear cells released very low amounts of 5(S)- and 12(S)-hydroxy-eicosatetraenoic acid (HETE), whereas endogenous 15(S)-HETE was found in substantial amounts. The transformation of exogenous 15(S)-HETE into 5(S),15(S)-diHETE and lipoxins was significantly more important in untreated asthmatic subjects than in control subjects and glucocorticoid-dependent asthmatic subjects. CONCLUSION: This study showed that long-term oral corticotherapy affects the 5-LO activity and leads to a decrease production of all metabolites in contrast to short-term or inhaled glucocorticoids. This study also questions the site of action of glucocorticoids in regulating the availability of arachidonic acid and potential eicosanoid regulation, as previously held in phospholipase A2 studies.

5-Lipoxygenase-Activating Proteins↗
PubMed2000

[Corticosteroid therapy of asthma].

UNLABELLED: BRONCHIAL INFLAMMATION AND GLUCOCORTICOIDS: Bronchial inflammation plays an important role in asthma and contributes to bronchoconstriction, hypersecretion and bronchial hyperreactivity. Glucocorticoids are the gold standard treatment in asthma affecting most of the components involved in bronchial inflammation. Inhaled steroids are recommended early in most countries. MECHANISM OF ACTION: The molecular and cellular mechanisms of glucocorticoids action are still better understood. However, it remains difficult to evaluate individual sensitivity when initiating treatment. Glucocorticoids have an effect on all inflammatory cells and bronchial structure cells. They bind to cytoplasmic receptors and then the complex links to DNA, inducing or inhibiting gene transcription in the target cell. DIFFERENT GLUCOCORTICOID SENSITIVITY: Very few patients are totally insensitive to the effect of glucocorticoids and require specific explorations for an identification. Although individual variability in corticosensitivity is similar in asthmatic patients and in the general population, the underlying mechanisms remain to be fully elucidated. The difference observed between responders and non-responders is not clearly identified and their definitions must be fully adapted.

Administration, Inhalation↗
PubMed2000

Glucocorticoid receptor alpha and beta in glucocorticoid dependent asthma.

Patients with glucocorticoid (GC)-dependent asthma present an ongoing inflammation of the airways despite chronic long-term treatment with oral GC. Interleukin (IL)-8 and granulocyte/macrophage colony-stimulating factor (GM-CSF) have been implicated in airway inflammation in severe asthma and their synthesis is normally repressed by GC. To further characterize the inflammatory process in GC-dependent asthma, we measured the release of IL-8 and GM-CSF by peripheral blood mononuclear cells (PBMC) of eight normal subjects, six untreated controlled asthmatics, six untreated uncontrolled asthmatics, and nine GC-dependent asthmatics. We show that PBMC from GC-dependent asthmatics released high amounts of these cytokines despite chronic in vivo exposure to GC (p < 0.001 versus normal subjects). In contrast, when untreated uncontrolled asthmatics were given a short course of oral GC, IL-8 and GM-CSF production was inhibited (p = 0.0078). Release of IL-8 and GM-CSF by PBMC of GC-dependent asthmatics was reduced after in vitro GC treatment (p < 0.002). We investigated whether the incapacity of GC to inhibit production of these cytokines in vivo was the result of a dysregulation of the glucocorticoid receptor (GR) in GC-dependent asthma. GRalpha and GRbeta are, respectively, the functional receptor and a putative dominant negative form of the receptor. Western blot and polymerase chain reaction (PCR) analyses indicated that GRalpha was expressed at similar level in all groups and was largely predominant over GRbeta. Thus, persistent release of IL-8 and GM-CSF in GC-dependent asthma is not associated with low expression of GRalpha or overexpression of GRbeta.

Adult↗
PubMed1999

Safety and cellular assessment of bronchial brushing in airway diseases.

Bronchial brushing is a useful method for morphological and functional studies of bronchial epithelial cells (BECs) in various diseases. This technique has been found to be generally safe, but its safety in asthma and chronic bronchitis has not been fully assessed. The purpose of this study was to determine 1, whether bronchial brushing is a safe method in asthmatic and chronic bronchitis patients of differing severity and 2, to characterize the BECs obtained in terms of number, viability and purity. We evaluated 25 asthmatics of variable severity, 19 chronic bronchitis patients and 26 normal volunteers. Bronchoscopy and bronchial brushing were performed in a standardized manner by the same investigator. Safety was assessed by clinical follow-up of all subjects; continuous monitoring of arterial oxygen saturation during the procedure with a digital oximeter was carried out in a subsample of subjects. No complications were observed clinically during the procedure. There was a minimal fall in arterial oxygen saturation without a significant difference between the three groups of subjects. A consistent number of BECs was recovered and their viability, assessed by the trypan blue exclusion test, in asthmatics and chronic bronchitis patients was significantly lower than in controls (P < 0.05). Bronchial brushing is well tolerated and may be a valuable method of obtaining BECs in asthmatic and chronic bronchitis patients.

Adult↗
PubMed1998

Generation of eicosanoids from 15(S)-hydroxyeicosatetraenoic acid in blood monocytes from steroid-dependent asthmatic patients.

The aim of this study was to investigate eicosanoid metabolism by human peripheral blood monocytes (PBM) from steroid-dependent asthmatic patients as compared to control subjects and untreated asthmatic patients. Eicosanoid biosynthesis by PBM isolated from venous blood using Percoll gradient centrifugation was evaluated following stimulation of 5 x 10(6) cells with calcium ionophore A23187, with or without exogenous 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), and analyzed by reverse phase high performance liquid chromatography (RP-HPLC). Without 15(S)-HETE, PBM synthesized leukotriene B4 (LTB4) only (40 +/- 12 ng and 59 +/- 11 ng for untreated and steroid-dependent asthmatics, respectively). In the presence of 15(S)-HETE, PBM produced six-fold smaller amounts of leukotriene B4 (P < 0.0001). They also released 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE) in similar amounts for all the populations, whereas low amounts of lipoxins (LXs) were produced by PBM from asthmatics only (2.7 +/- 0.7 ng and 4.6 +/- 2.8 ng for untreated and steroid-dependent asthmatics, respectively). Moreover, PBM were also able to release an unknown compound containing conjugated triene chromophore. Cells from steroid-dependent asthmatic patients synthesized this unknown metabolite in higher amounts than controls and untreated asthmatics (133 +/- 18 ng vs 52 +/- 19 ng and 68 +/- 15 ng, respectively, P < 0.02). This work shows for the first time that human PBM are able to metabolize 15(S)-HETE and lead to lipoxins and to an unknown metabolite, with the amounts of the latter being enhanced by long-term corticosteroid treatment.

Adrenal Cortex Hormones↗
PubMed1998

Glucocorticoid receptors in bronchial epithelial cells in asthma.

The expression of the glucocorticoid receptor (GR) in untreated or in steroid-dependent asthmatic patients is poorly understood. We therefore studied GR mRNA and protein levels in bronchial biopsies obtained from seven untreated asthmatic patients, seven control volunteers, and seven patients with chronic bronchitis. We also studied in bronchial epithelial cells obtained by brushing from 13 untreated asthmatics, 18 steroid-dependent asthmatics, 11 control volunteers, and 12 patients with chronic bronchitis, GR and heat shock protein 90 kD (hsp90) mRNA as well as the immunoreactivity of GR, intercellular adhesion molecule (ICAM-1), and granulocyte macrophage-colony-stimulating factor (GM-CSF). GR mRNA and protein level was similar in all subject groups in both biopsies and bronchial epithelial cells. Hsp90 mRNA level was also similar in all subject groups. ICAM-1 expression was significantly increased in bronchial epithelial cells from untreated asthmatics, but ICAM-1 was not expressed in those from steroid-dependent asthmatic patients. GM-CSF expression was significantly increased in bronchial epithelial cells from untreated and steroid-dependent asthmatic patients. GR expression within the airways is unaltered by oral long-term steroid treatment in asthma, but the expression of some but not all specific markers for asthma is modified by oral steroid.

Administration, Oral↗
PubMed1998

Expression of the high-affinity receptor for IgE on bronchial epithelial cells of asthmatics.

Bronchial epithelial cells are the first cells to come into contact with inhaled pneumoallergens. It has been suggested that these cells may play an important role in the allergic response, and indeed bronchial epithelial cells of some atopic asthmatic subjects have been shown to express the low-affinity receptor for IgE on their surface. In this report we demonstrate, using bronchial biopsies, that bronchial epithelial cells of some asthmatic subjects express both the alpha and gamma chains of the high-affinity receptor for IgE (Fcepsilon RI) on their surface and that they are capable of fixing IgE. Second, using reverse transcription-polymerase chain reaction, we show that both control and asthmatic subjects have messenger RNA for Fcepsilon RI. Finally, we demonstrate that this receptor may be functional since stimulation of the cells with the antibody to the alpha chain of Fcepsilon RI results in the liberation of 15-hydroxyeicosatetraenoic acid from epithelial cells of asthmatic, but not control, subjects or subjects suffering from chronic bronchitis. These data suggest that bronchial epithelial cells from at least some asthmatic subjects express a functional high-affinity receptor for IgE and it is therefore possible that these cells may be able to interact directly with inhaled allergens.

Adolescent↗
PubMed1998

Superoxide anion production by monocytes of corticosteroid-treated asthmatic patients.

Reactive oxygen species play an important role in promoting inflammation. Blood monocytes have been described to release higher amounts of superoxide anion in uncontrolled and untreated asthmatics. Corticosteroids are widely used in asthma, but little is known about their molecular mechanism of action. The aim of our study was to analyse the ex vivo effect of corticosteroid treatments on superoxide anion release by blood monocytes. Superoxide anion release was measured by a spectrophotometric method based on the superoxide dismutase (SOD) -inhibitable reduction of ferricytochrome C by blood monocytes from untreated patients and asthmatics treated with i.v., inhaled and oral corticosteroids. Monocytes from uncontrolled and untreated asthmatics, released high amounts of superoxide anions. After short-term treatment with i.v., corticosteroids, this release was found to decrease significantly (1.410 versus 0.340 nM, p<0.05). Cells from asthmatics who had undergone long-term treatment with inhaled or oral steroids presented low amounts of superoxide anion production, with a significant difference as compared to untreated asthmatics (0.375 nM p<0.01 and 0.620 nM p<0.02 respectively). In general, patients with controlled asthma (treated with short-term oral steroids, or with long-term inhaled steroids) released lesser amounts of superoxide anion than uncontrolled and untreated asthmatics. In the case of steroid-dependent asthmatics there was no difference between patients with a controlled or uncontrolled disease.

Administration, Inhalation↗