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Biomedical subjects

P Demoly

Publications and source records attributed to P Demoly.

At least 109 records · Page 6Linked to original sources
PubMed1999

The glucocorticoid receptor gene as a candidate for gene therapy in asthma.

Glucocorticoids (GC) are commonly used as anti-inflammatory drugs in asthma, but can produce serious secondary effects and, moreover, be inefficient in corticoresistant asthmatics. After binding to the glucocorticoid receptor (GR), they repress the synthesis of proinflammatory cytokines via inhibition of the transcription factors AP-1 and NF-kappa B. Since qualitative and quantitative defects of the GR have been reported in corticoresistant patients, the transfer of the GR gene in the lung epithelium, the primary site of inflammation in asthma, may restore sensitivity to GC in these patients. As a prerequisite to in vivo studies, we have transfected A549 human lung epithelial cells with a GR expression vector. Using AP-1 and NF-kappa B-dependent reporter gene assays and an immunoassay for the pro-inflammatory cytokine RANTES, we show that the over-expressed GR significantly repressed AP-1 and NF-kappa B activities in the absence of hormone and that the GC dexamethasone produced an additive inhibitory effect. The GC-independent repression of AP-1 and NF-kappa B activities was further demonstrated by overexpressing a ligand-binding deficient GR mutant. Our data suggest that delivery of the GR gene in vivo may reduce inflammation without recourse to GC and may constitute an alternative therapeutic approach for corticoresistant asthma.

Animals↗
PubMed1999

VEGF levels in asthmatic airways do not correlate with plasma extravasation.

BACKGROUND: Vascular permeability/vascular endothelial growth factor (VEGF) is a multifunctional cytokine which plays a role in chronic inflammation and angiogenesis. Its expression in bronchoalveolar lavage (BAL) has not been determined although VEGF may be relevant to the pathophysiology of asthma in which oedema is an important feature. METHODS: We studied VEGF, albumin and IgA immunoreactive levels in the BAL fluids obtained from 27 chronic stable asthmatics, nine untreated chronic bronchitis patients and 15 control subjects. RESULTS: BAL fluid levels of VEGF and VEGF normalized to IgA were not significantly different in any patient group. Both asthmatic steroid- and non-steroid-treated groups had significantly lower albumin levels in their BAL fluids explaining most of the 179% increased VEGF normalized to albumin ratios in non-steroid treated asthmatics. Moreover, VEGF and albumin markers correlated in control subjects (r = 0.73, P = 0.006) and in chronic bronchitics (r = 0.75, P = 0.03, Spearman test), but not in asthmatics. VEGF was inversely correlated with asthma severity (GINA/NHLBI scores) in non-steroid treated asthmatics (tau = - 0.52, P = 0.009, Kendall test). CONCLUSIONS: Thus, the potential role of VEGF in asthma requires further studies on bronchial biopsies and induced sputum.

Adult↗
PubMed1999

Rifampicin is not an activator of the glucocorticoid receptor in A549 human alveolar cells.

It has recently been reported that rifampicin activates the glucocorticoid receptor and acts as an immunosuppressive drug. Because rifampicin constitutes an essential part of pulmonary tuberculosis therapy, we have examined whether it triggers glucocorticoid-like effects in alveolar cells. We have used reporter gene assays to measure the trans-activating and trans-repressing capacity of the glucocorticoid receptor after treating A549 human alveolar cells with rifampicin. The data show that rifampicin neither activated transcription from a promoter containing a glucocorticoid response element nor repressed the activity of activator protein 1 and nuclear factor kappaB, which are transcription factors involved in the immune response. In addition, rifampicin was also unable to inhibit the expression of an endogenous gene that contains activator protein 1 and nuclear factor kappaB response elements and encodes the proinflammatory cytokine RANTES (regulated upon activation normal T expressed and secreted protein). Finally, nuclear translocation of the glucocorticoid receptor, which occurs after ligand binding, was not triggered by rifampicin. In contrast, the glucocorticoid dexamethasone scored positive in all corresponding control experiments. In conclusion, rifampicin is not an activator of the glucocorticoid receptor in A549 alveolar cells. Our results support the clinical observation that rifampicin is not an immunosuppressive drug and suggest that the current medical practice concerning this antibiotic should not be changed.

Antibiotics, Antitubercular↗
PubMed1999

[Immunobiology of respiratory allergy].

Respiratory allergies are frequent and the etiological diagnosis is not always easy. Most often, the allergy assessment is vital. For the allergist, this assessment begins with skin tests which must be complemented by measurement of the level of specific IgE in case of doubt. For the generalist or physician who does not have special competence in allergy, an alternative to a specialist consultation at once is a multi-allergen test of detection. This assessment is necessary to set out the etiological diagnosis and facilitate the responsibility of the therapy.

Allergens↗
PubMed1999

Experimental models in rhinitis.

Nasal challenge with allergen or mediators is a useful model to understand the pathophysiology of allergic rhinitis. Some mechanisms have thereby been clearly clarified. Different methods have been proposed to mimic the natural allergen exposure and to measure the clinical and biological responses. Nasal challenges can also be used in clinical practice, mainly when there is a discrepancy between results of skin tests and in vitro or when occupational allergens are involved. Nasal challenges are also valuable to assess the efficacy of specific immunotherapy or some drugs.

Animals↗
PubMed1999

[Mechanism of action of glucocorticoids in asthma].

While on the basis of clinical studies glucocorticoids (GC) became the first-line therapy for asthma, the molecular basis of GC action has been extensively studied. Glucocorticoids exert their effects by binding to the glucocorticoid receptor (GR), which then inhibits or increases gene transcription through processes known as transrepression and transactivation, respectively. Transrepression results from the inhibitory interaction between the GR and other transcription factors like AP-1 and NF-kappa B. Since AP-1 and NF-kappa B DNA binding sites have been mapped to the promoter regions of many genes coding for proinflammatory mediators (IL-1, 2, 5, 6, 8, 13, TNF-alpha, RANTES, Eotaxin, GM-CSF, metalloproteinases, ICAM-1 ...), this interaction may be an important aspect of the GC anti-inflammatory properties. Transactivation is mediated through binding of the GC-activated GR to a DNA sequence called glucocorticoid response element (GRE) and may result in some benefits and side effects since GRE has been mapped to the promoter regions of genes coding for lipocortin, beta 2-adrenergic receptor, and for genes involved in the onset of metabolic effects (diabetes, hypokaliemia, hydrosodic retention) and glaucoma. Other molecular mechanisms may also be involved like the binding to the GR to a negative GRE (nGRE), the interaction with the basal transcriptional machinery, and the post transcriptional modulation of mRNA stability. In asthma, the relative importance of each mechanism remains to be studied, but both mechanisms may probably be involved.

Asthma↗
PubMed1998

[Drug allergies: management and current aspects].

UNLABELLED: ALLERGIC AND PSEUDOALLERGIC REACTIONS: Adverse drug reactions occur in 1 to 3% of hospitalized patients and 10% are due to allergic and pseudoallergic reactions. Allergic reactions are unpredictable reactions related to immunologic mechanism. Pseudoallergic reactions mimic allergic reactions but no drug-specific antibody or T cell proliferation can be demonstrated. PREVENTION: We are lacking clinical and biological tools and the available ones still need to be validated. However, a precise diagnosis is required in order to set up prevention measures. We focus here on some basic and new data concerning these reactions, in particular epidemiological studies, mechanisms and diagnostic methods.

Cross-Sectional Studies↗
PubMed1998

Adenovirus-mediated in vivo gene transfer in guinea pig middle ear mucosa.

This article describes a study designed to assess the feasibility of using recombinant adenovirus for delivering therapeutic peptides in vivo in the guinea pig middle ear cleft. A recombinant adenoviral vector AdCMVsp1 LacZ containing the Escherichia coli beta-galactosidase was injected into the middle ear space. Qualitative assessment of cell middle ear transfection was performed on day 2 by light microscopy study, after injecting a multiplicity of infection (MOI) ranging from 0 to 1000. At an MOI of 30, 30% of the promontory area epithelial cells were stained. An MOI of 50 stained 60% of the cells and an MOI of 100 or more stained more than 90% of the cells. The duration of cell transfection was studied after injecting an MOI of 50. The percentage of stained cells was 60% on day 2, 10% on day 7, and 0% on day 14. Middle ear mucosal inflammation, consisting of a granulocytic infiltrate, was observed when an MOI above 50 was used. Even at a high MOI (500), no staining could be found in the cochlea, in the facial nerve, in the brain, or in visceral organs. These data suggest that recombinant adenovirus vectors can be used to transfer genes in the middle ear. This method appears to be safe, and may be envisaged as a short-duration treatment to transfer genes in vivo in the treatment of middle ear diseases.

Adenoviridae↗
PubMed1998

Six-hour trimethoprim-sulfamethoxazole-graded challenge in HIV-infected patients.

BACKGROUND: Hypersensitivity reactions to trimethoprim-sulfamethoxazole (TMP-SMX) are very common in HIV-infected patients, leading to drug discontinuation. However, it is the drug of choice as prophylaxis for Pneumocystis carinii pneumonia. OBJECTIVES: We sought to determine the safety and long-term efficacy of a 6-hour TMP-SMX-graded challenge in a group of hypersensitive HIV-infected patients. METHODS: Forty-four consecutive HIV-infected patients with documented TMP-SMX hypersensitivity were seen in our outpatient allergy department. They ingested 12 doses of increasing amounts of TMP-SMX at half-hour intervals. Thereafter, they took 80/400 mg TMP-SMX daily and were advised to "treat through" every nonbullous cutaneous adverse reaction. RESULTS: All 44 patients tolerated the procedure without any adverse reactions during the day of challenge. Eleven of the 44 patients experienced mild hypersensitivity reactions on days 1 to 2 (8 patients) and 8 to 10 (3 patients), consisting mainly on a 1-day pruritic maculopapular eruption. Two patients stopped TMP-SMX at day 1, and 2 stopped it at days 10 and 15, giving an overall success rate at 1 month of 91% (40 of 44). Two were successfully rechallenged late. After a median follow-up of 10 months, 42 patients were taking TMP-SMX without any adverse reaction, giving an overall success rate of 95%. CONCLUSIONS: A 6-hour graded challenge with cautious "treating through" of mild reactions enables more patients to take TMP-SMX and is safe and effective.

Administration, Oral↗
PubMed1998

The use of home nebulizers in adult asthma.

Nebulization therapy is an approach for the treatment of respiratory diseases such as asthma which was not anticipated in the international recommendations for the treatment of asthma and which merits study. Even if the place of nebulizers in the treatment of asthma exacerbations has been validated, this is not the case for adult asthmatic subjects with chronic asthma. While asthma control for most patients can be achieved using metered-dose inhaler and dry powder inhaler therapy, some patients may require regular home nebulized therapy. Before determining the objectives and therapeutic characteristics of nebulization in the treatment of chronic asthma in the adult patient, we shall first describe the pathophysiological elements involved in the treatment of asthma and of the couple 'nebulized substance-nebulizer' leading to an optimal nebulization.

Adult↗
PubMed1998

Expression of cyclo-oxygenase 1 and 2 proteins in upper respiratory mucosa.

BACKGROUND: Cyclo-oxygenases 1 (Cox-1) and 2 (Cox-2) catalyse the conversion of arachidonic acid to prostaglandin endoperoxides, leading to the formation of prostaglandin and thromboxane mediators of inflammation. The involvement of these enzymes in inflammatory disorders such as sinusitis and nasal polyps is unknown although this may be relevant to their pathophysiology. METHODS: We studied Cox-1 and Cox-2 immunoreactivities in nasal polyp, maxillary sinus, and turbinate biopsies obtained from eight patients with chronic allergic rhinitis and sinusitis and/or nasal polyps, 15 patients with chronic non-allergic rhinitis and sinusitis and/or nasal polyps and five control subjects (patients requiring nose surgery not related to sinusitis or nasal polyps). RESULTS: Both Cox- and Cox-2 were mainly expressed in the epithelium (basal, ciliated) and were found in 16/28 and 25/28 subjects for Cox-1 and Cox-2 respectively. We did not find any differences between the patient populations. There were no correlations between any of the clinical parameters studied nor the pathological patterns and the presence and characteristics of the Cox immunoreactivities. CONCLUSION: Both cyclo-oxygenase enzymes are expressed in normal human upper respiratory epithelium and are not upregulated in chronic sinusitis nor in nasal polyposis, possibly suggesting that Cox products do not have an important role as mediators of the chronic upper airway inflammation.

Adolescent↗