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Biomedical subjects

J M Drazen

Publications and source records attributed to J M Drazen.

At least 109 records · Page 6Linked to original sources
PubMed1997

Interferon gamma induces prostaglandin G/H synthase-2 through an autocrine loop via the epidermal growth factor receptor in human bronchial epithelial cells.

The induction of prostaglandin G/H synthase (PGHS; prostaglandin endoperoxide synthase, cyclooxygenase) by proinflammatory cytokines accounts, at least in part, for the altered eicosanoid biosynthesis in inflammatory diseases. In secondary cultures of normal human bronchial epithelial cells (NHBECs), interferon-gamma (IFN-gamma, 10 ng/ml for 24 h) increased the amount of prostaglandin E2 (PGE2) released in response to stimulation with exogenous arachidonic acid (5 microM). The enhanced production of PGE2 reflected the upregulation of PGHS-2 as indicated by enhanced expression of PGHS-2 RNA and increased recovery of PGHS-2 protein in NHBECs. IFN-gamma did not alter the production of PGE2 in A549 cells (a human lung adenocarcinoma cell line) or 6-keto-PGF1alpha in human umbilical vein endothelial cells (HUVECs), although prostaglandin release and/or the expression of PGHS-2 RNA in these cell lines was upregulated by other proinflammatory cytokines. Induction of PGHS-2 RNA in IFN-gamma-treated NHBECs, which peaked at 24 h, suggested the presence of an intermediary substance regulating the expression of PGHS-2. When the binding between the epidermal growth factor (EGF) receptor and its ligands was disrupted by a neutralizing antibody (LA-1), IFN-gamma failed to upregulate the release of PGE2 and the expression of PGHS-2 RNA in NHBECs. Furthermore, IFN-gamma induced the expression of RNAs for a number of ligands at the EGF receptor TGF-alpha; heparin-binding EGF-like growth factor (HB-EGF); and amphiregulin in NHBECs, and when administered exogenously, these ligands increased PGE2 release from NHBECs. Heparin at the concentration that neutralized the function of amphiregulin, or antibodies against TGFalpha or HB-EGF also reduced the release of PGE2 from IFN-gamma-stimulated NHBECs. These data are consistent with the presence of an autocrine growth factor/EGF receptor loop regulating PGHS-2 expression and PGE2 synthesis in bronchial epithelial cells.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription.

Five lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes. We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene. A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.

Alleles↗
PubMed1997

T-lymphocytes regulate genetically determined airway hyperresponsiveness in mice.

Airway hyperresponsiveness (AHR) is a hallmark of asthma and a heritable polygenic trait in the mouse. In the mouse, candidate gene products of hematopoietic origin implicated in asthma mapped to the regions of the previously defined quantitative trait loci. Since hematopoietic cells have been implicated in the pathogenesis of asthma, we evaluated the role of hematopoietic cells in general and T cells specifically in the genetic modulation of native airway responsiveness in mice. Here, with the use of bone marrow transplantation, anti-T-cell monoclonal antibody treatment and T-cell transfer, we demonstrate that intrinsic non-atopic AHR is mediated by T lymphocytes. Our data support the novel concept that, in the absence of identified environmental influences, T cells enhance genetically determined airway responsiveness.

Adoptive Transfer↗
PubMed1997

Acute and chronic effects of allergic airway inflammation on pulmonary nitric oxide production.

Nitric oxide (NO) is thought to be an important modulator of airway function in normal and inflamed airways. We investigated the acute and chronic effects of induced allergic airway inflammation on NO levels in mixed expired gas and NO synthase (NOS) expression in guinea pigs and the relationship between airway responses and NO production. Airway inflammation was induced by repeated aerosolized antigen exposure, and its presence was confirmed by bronchoalveolar lavage. Acute antigen exposure in sensitized animals produced a fivefold increase in respiratory resistance over baseline that was associated with a cotemporal increase in expired NO (17 +/- 1 to 56 +/- 8 parts per billion, P < 0.01). A continuous subcutaneous infusion of nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NOS, markedly decreased expired NO (P < 0.01) and resulted in a significantly greater rise in resistance following antigen challenge (660 +/- 60 vs. 497 +/- 42% of baseline in non-L-NAME-treated animals, P < 0.05). These data support the hypothesis that endogenous pulmonary NO production, as reflected by expired NO, has an important homeostatic role in acute allergic bronchoconstriction.

Acute Disease↗
PubMed1997

Endogenous nitric oxide and allergic bronchial hyperresponsiveness in guinea pigs.

To address the role of endogenous pulmonary nitric oxide (NO) in the modulation of airway tone, we investigated changes in expired NO levels, measured by chemiluminescence, and the effect of inhibition of NO synthase on inflammation-associated bronchial hyperresponsiveness in guinea pigs. Mixed expired gas NO levels were similar at baseline in antigen-exposed and unexposed animals and increased transiently to a similar degree during histamine-induced bronchoconstriction in both groups of animals [155 +/- 12% (15 +/- 1 to 23 +/- 4 ppb, P < 0.01) and 162 +/- 19% (16 +/- 2 to 25 +/- 3 ppb, P < 0.01) of baseline, respectively, after administration of 30 nmol/kg histamine]. Although inhibition of NO synthase with intravenous NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) enhanced bronchial responsiveness to histamine by 30 +/- 8% in unexposed animals (P < 0.05), L-NAME did not enhance histamine responsiveness in antigen-exposed animals exhibiting bronchial hyperresponsiveness 24 h after antigen exposure. Thus bronchial hyperresponsiveness induced by repeated pulmonary antigen exposure may be associated with a transient defect in NO-related homeostatic bronchodilator activity.

Animals↗
PubMed1997

Contribution of type I NOS to expired gas NO and bronchial responsiveness in mice.

Nitric oxide (NO) can be measured in the expired gas of humans and animals, but the source of expired NO (F(E)NO) and the functional contribution of the various known isoforms of NO synthase (NOS) to the NO measured in the expired air is not known. F(E)NO was measured in the expired air of mice during mechanical ventilation via a tracheal cannula. F(E)NO was significantly higher in wild-type B6SV129J +/+ mice than in mice with a targeted deletion of type I (neural) NOS (nNOS, -/-) (6.3 +/- 0.9 vs. 3.9 +/- 0.4 parts/billion, P = 0.0345, for +/+ and -/- mice, respectively), indicating that approximately 40% of the NO in expired air in B6SV129 mice is derived from nNOS. Airway responsiveness to methacholine (MCh), assessed by the log of the effective dose of MCh for a doubling of pulmonary resistance from baseline (ED(200)R(L)), was significantly lower in the -/- nNOS mice than in the wild-type mice (logED(200)R(L), 2.24 +/- 0.07 vs. 2.51 +/- 0.06 microg/kg, respectively; P = 0.003). These findings indicate that nNOS significantly contributes to baseline F(E)NO and promotes airway hyperresponsiveness in the mouse.

Animals↗
PubMed1997

Respiratory transfer impedance between 8 and 384 Hz in guinea pigs before and after bronchial challenge.

We report a forced oscillatory technique for noninvasively measuring respiratory transfer impedance (Ztr) between 8 and 384 Hz in guinea pigs. This technique uses a device consisting of two chambers: one surrounding the animal's head that is used as a plethysmograph to measured flow through the airway opening and the other that surrounds the animal's body and is used to apply pressure oscillations to the body surface. Ztr was measured in spontaneously breathing awake guinea pigs and while the animals were anesthetized in normal and methacholine-challenged conditions. An eight-element model consisting of an airway compartment separated from a tissue compartment by a shunt gas compression compartment was fit to the data. Anesthesia increased central and peripheral airway resistance and bronchial airway wall compliance by 13, 31, and 44%, respectively, whereas it decreased tissue compliance by 37%. Compared with the unanesthetized condition, the methacholine challenge (20 micrograms/kg) resulted in an increase in central and peripheral airway resistance (69 and 319%, respectively) and a decrease in bronchial airway wall and tissue compliance (37 and 79%, respectively). This technique is capable of measuring Ztr in anesthetized and awake guinea pigs. Analysis of these data with this eight-element model provides reasonable estimates of airway and tissue parameters.

Airway Resistance↗
PubMed1997

Reduction of allergic airway responses in P-selectin-deficient mice.

P-selectin is an adhesion receptor that has been shown to be important in the recruitment of eosinophils and lymphocytes in a variety of inflammatory conditions. Because cellular recruitment is thought to be a critical event in allergen-induced changes in airway responsiveness, we reasoned that P-selectin-deficient mice would exhibit reduced airway responsiveness and cellular trafficking noted in wild-type (+/+) mice. Both (+/+) and P-selectin-deficient (-/-) mice sensitized and challenged with ovalbumin (OVA/OVA) exhibited the same capacity to produce increased titers of total and OVA-specific immunoglobulin E. Airway responsiveness to methacholine was significantly greater in the (+/+) (OVA/OVA) animals than it was in the respective (-/-) (OVA/OVA) group or control groups (P = 0.0016). Bronchoalveolar lavage fluid from (-/-) (OVA/OVA) mice contained significantly fewer eosinophils and lymphocytes compared with the (+/+) (OVA/OVA) mice (P < 0.05). These results suggest that the predominant role of P-selectin in OVA-induced airway hyperresponsiveness is to promote the airway inflammatory response to allergen inhalation.

Airway Resistance↗
PubMed1997

On the mechanism of mucosal folding in normal and asthmatic airways.

Previous studies have demonstrated that the airway wall in asthma and chronic obstructive pulmonary disease is markedly thickened. It has also been observed that when the smooth muscle constricts the mucosa buckles, forming folds that penetrate into the airway lumen. This folding pattern may influence the amount of luminal obstruction associated with smooth muscle activation. A finite-element analysis of a two-layer composite model for an airway is used to investigate the factors that determine the mucosal folding pattern and how it is altered as a result of changes in the thickness or stiffness of the different layers that comprise the airway wall. Results demonstrate that the most critical physical characteristic is the thickness of the thin inner layer of the model. Thickening of this inner layer likely is represented by the enhanced subepithelial collagen deposition seen in asthma. Other findings show a high shear stress at or near the epithelial layer, which may explain the pronounced epithelial sloughing that occurs in asthma, and steep gradients in pressure that could cause significant shifts of liquid between wall compartments or between the wall and luminal or vascular spaces.

Asthma↗
PubMed1997

Genetics of native airway responsiveness in mice.

The inbred mouse represents a powerful tool for dissecting both simple and complex traits. Genetic studies in the mouse should identify disease genes acting in the same biochemical pathway as in the human. Problems associated with genetic heterogeneity, inability to control environmental conditions, lack of an abundant supply of genetic markers, and ethical considerations regarding human genetic crosses are but some of the reasons to study airway responsiveness in the mouse. At present, only a handful of studies have shed light on the genetics of airway responsiveness; even fewer have sought to identify genetic loci that regulate this trait. It is clear that both genetic and environmental factors influence the asthma phenotype and that genetic background is an important consideration when interpreting segregation analysis data. The controversy over the specific mode of inheritance and number and location of quantitative trait loci (QTL) illustrates the need for additional studies. However, given that numerous candidate loci implicated in the pathogenesis of asthma map near QTLs identified in two recent studies, and given the considerable homology between the human and mouse genome, a targeted search for susceptibility genes is warranted in the human. Ideally, these regions will demonstrate linkage in humans. Thus, further work remains to be done to create detailed maps of the regions of linkage in the mouse, and to ultimately identify gene(s) that modify airway responsiveness. mice.

Animals↗
PubMed1997

An evaluation of colchicine as an alternative to inhaled corticosteriods in moderate asthma. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network.

Colchicine demonstrates an array of anti-inflammatory properties of potential relevance to asthma. However, the efficacy of colchicine as an alternative to inhaled corticosteroid therapy for asthma is unknown. Five centers participated in a controlled trial testing the hypothesis that in patients with moderate asthma needing inhaled corticosteroids for control, colchicine provides therapeutic benefit as measured by maintenance of control when inhaled steroids are discontinued. Subjects were stabilized on triamcinolane acetonide (800 microg daily) and then enrolled in a 2-wk run-in during which all subjects took both colchicine (0.6 mg/twice a day) and triamcinolone. At the end of the run-in, all subjects discontinued triamcinolone and were randomized to continued colchicine (n = 35) or placebo (n = 36) for a 6-wk double-blind treatment period. The treatment groups were similar in terms of disease severity. After corticosteroid withdrawal, 60% of colchicine-treated and 56% of placebo-treated subjects were considered treatment failures as defined by preset criteria. No significant difference in survival curves was found between treatment groups (log rank = 0.38). Other measures, including changes in FEV1, peak expiratory flow, symptoms, rescue albuterol use, and quality of life scores, also did not differ between groups. Of note, subjects failing treatment had significantly greater methacholine responsiveness at baseline than did survivors (PC20, 0.81+/-1.38 versus 2.11+/-2.74 mg/ml; p = 0.01). An analysis of treatment failures suggested that the criteria selected for failure reflected a clinically meaningful but safe level of deterioration. We conclude that colchicine is no better than placebo as an alternative to inhaled corticosteroids in patients with moderate asthma. Additionally, we conclude that the use of treatment failure as the primary outcome variable in an asthma clinical trial where treatment is withdrawn is feasible and safe under carefully monitored conditions.

Administration, Inhalation↗
PubMed1996

Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network.

BACKGROUND: Inhaled beta-agonists are the most commonly used treatment for asthma, but data suggest that regularly scheduled use of these agents may have deleterious effect on the control of asthma. We compared the effects of regularly scheduled use of inhaled albuterol with those of albuterol used only as needed in patients with mild chronic, stable asthma. METHODS: In a multicenter, double-blind study, we randomly assigned 255 patients with mild asthma to inhale albuterol either on a regular schedule (126 patients) or only as needed (129 patients). The patients were followed for 16 weeks. RESULTS: The primary outcome indicator, peak expiratory air flow measured in the morning, did not change significantly during the treatment period in the scheduled (416 liters per minute after the run-in period and 414 liters per minute after the treatment period) or the as-needed (424 liters per minute at both times) treatment groups (P=0.71). There were no significant differences between the two groups in peak flow variability, forced expiratory volume in one second, the number of puffs of supplemental albuterol needed, asthma symptoms, asthma quality-of-life score, or airway responsiveness to methacholine. The statistically significant differences between the groups in evening peak flow and in the short-term bronchodilator response to inhaled albuterol were small and judged to be clinically unimportant. CONCLUSIONS: In patients with mild asthma, neither deleterious nor beneficial effects derived from the regular use of inhaled albuterol beyond those derived from use of the drug as needed. Inhaled albuterol should be prescribed for patients with mild asthma on an as-needed basis.

Administration, Inhalation↗
PubMed1996

Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group.

OBJECTIVE: To study the effect of 3 months of treatment with zileuton, an inhibitor of the enzymatic pathway (5-lipoxygenase) leading to leukotriene formation, on disease control in patients with mild to moderate asthma. DESIGN: Randomized, double-blind, parallel-group study in 401 patients. A 10-day placebo lead-in was followed by a double-blind treatment period of 13 weeks. SETTING: Asthma study clinics in university hospitals and private practices. PATIENTS OR OTHER PARTICIPANTS: Patients with mild to moderate asthma (forced expiratory volume in the first second [FEV1], 40% to 80% of predicted) whose only treatment was inhaled beta-agonists. INTERVENTIONS: Treatment with 600 mg or 400 mg of zileuton or placebo (each taken four times daily.) MAIN OUTCOME MEASURES: Frequency of asthma exacerbation requiring treatment with corticosteroids, use of inhaled beta-agonists, pulmonary function tests, asthma symptom assessment, and quality-of-life evaluation. Safety was evaluated by monitoring adverse events. RESULTS: Only eight (6.1%) of 132 patients receiving 600 mg of zileuton four times a day required corticosteroid treatment for asthma vs 21 (15.6%) of 135 patients receiving placebo (P=.02), giving a relative risk of 2.6. At the time of expected peak drug concentration, the average FEV1 improved 15.7% in the 600-mg zileuton group vs 7.7% in the placebo group (P=.006). Quality-of-life assessments significantly improved in the 600-mg zileuton group and not in the placebo group (P=.007 for the overall score). Elevations in liver function tests (more than three times normal), all of which reversed with drug withdrawal, occurred in five patients (P=.03 vs placebo), three patients (P=.12 vs placebo), and no patients treated with 600 mg of zileuton, 400 mg of zileuton, or placebo, respectively. CONCLUSIONS: Three months of 5-lipoxygenase inhibition produced a significant improvement in asthma control. These data indicate that 5-lipoxygenase products of arachidonic acid metabolism are mediators of inflammation with an important role in the biology of asthma.

Adrenergic beta-Agonists↗