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J M Drazen

Publications and source records attributed to J M Drazen.

At least 73 records · Page 4Linked to original sources
PubMed1999

Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma.

Asthma is a chronic disease characterized by increased airway responsiveness and airway inflammation. The functional role of nitric oxide (NO) and the various nitric oxide synthase (NOS) isoforms in human asthma is controversial. To investigate the role of NO in an established model of allergic asthma, mice with targeted deletions of the three known isoforms of NOS (NOS1, 2, and 3) were studied. Although the inducible (NOS2) isoform was significantly upregulated in the lungs of ovalbumin (OVA)-sensitized and -challenged (OVA/OVA) wild-type (WT) mice and was undetectable in similarly treated NOS2-deficient mice, airway responsiveness was not significantly different between these groups. OVA/OVA endothelial (NOS3)-deficient mice were significantly more responsive to methacholine challenge compared with similarly treated NOS1 and NOS1&3-deficient mice. Airway responsiveness in OVA/OVA neuronal (NOS1)-deficient and neuronal/endothelial (NOS1&3) double-deficient mice was significantly less than that observed in similarly treated NOS2 and WT groups. These findings demonstrate an important function for the nNOS isoform in controlling the inducibility of airway hyperresponsiveness in this model of allergic asthma.

Animals↗
PubMed1999

Cytogenetic and radiation hybrid mapping of human arachidonate 5-lipoxygenase-activating protein (ALOX5AP) to chromosome 13q12.

Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) is an arachidonic acid binding protein that has been shown to be critical in the biosynthesis of leukotrienes. We mapped the ALOX5AP gene to the chromosome 13q12 region by cytogenetic mapping, yeast artificial chromosome (YAC) pool screening, and radiation hybrid mapping. It was mapped to YAC contig WC13.2 by YAC pool screening with an unambiguous hit to WI-4874, which is at 78 cR on the radiation hybrid map, 3.36 cR, by radiation hybrid mapping, from WI-4874.

5-Lipoxygenase-Activating Proteins↗
PubMed1999

Elevated plasma eotaxin levels in patients with acute asthma.

BACKGROUND: The eosinophil chemotactic and activating effects of eotaxin and the known association of eosinophils with asthma suggest that eotaxin expression is increased during asthma exacerbations. OBJECTIVE: We sought to determine whether plasma eotaxin levels are elevated in patients presenting for emergency treatment of acute asthma and to correlate eotaxin levels with disease activity and responses to treatment. METHODS: A case-control study of plasma eotaxin levels was performed in the 46 patients who presented for emergency asthma treatment and 133 age-, sex-, and ethnicity-matched subjects with stable asthma. RESULTS: Plasma eotaxin levels were significantly higher in 46 patients with acute asthma symptoms and airflow obstruction (520 pg/mL [250, 1100 pg/mL]; geometric mean [-1 SD, +1 SD]) than in 133 subjects with stable asthma (350 pg/mL [190, 620 pg/mL]; P =.0008). Among the patients with emergency asthma flares, those who responded to asthma treatment with an increase in peak expiratory flow rate by an amount equal to at least 20% of their predicted normal value had lower eotaxin levels than those who did not (410 pg/mL [210, 800 pg/mL] and 660 pg/mL [300, 1480 pg/mL], respectively; P =.04). CONCLUSION: These findings imply that eotaxin either is mechanistically involved in acute asthma or serves as a biomarker for activity of the CCR3 receptor ligand system, which is functionally linked to asthma.

Acute Disease↗
PubMed1999

Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment.

Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway provide a method to identify those patients in whom the products of the ALOX5 pathway (that is, the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. We previously defined a family of DNA sequence variants in the core promoter of the gene ALOX5 (on chromosome 10q11.2) associated with diminished promoter-reporter activity in tissue culture. Because expression of ALOX5 is in part transcriptionally regulated, we reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and drug-treatment responses, that is, a pharmacogenetic effect of a promoter sequence on treatment responses.

Alleles↗
PubMed1999

Animal models of asthma and chronic bronchitis.

Human asthma is characterized by three critical phenotypic traits: intermittent reversible airway obstruction, airway hyperresponsiveness and airway inflammation. In animal models of asthma, airway hyperresponsiveness is an important feature. This trait is characterized by an exaggerated bronchoconstrictor response that would have little physiological consequence in an otherwise unaffected or normal individual. In this article we explore two distinct facets of airway responsiveness. The first is the genetic basis for variations in airway responsiveness that occur in mice in the absence of any specific environmental manipulation. We demonstrate that standard genetic approaches can be successfully applied to the identification of regions of the mouse genome linked to the expression of airway hyperresponsiveness. The second topic addressed in this review is the change in airway responsiveness induced in rats by repeated exposure to sulphur dioxide gas. With daily exposure to high concentrations of sulphur dioxide gas, there is chronic injury and repair of epithelial cells. Over time, rats develop mucous hypersecretion, airway inflammation, increased airway resistance and airway hyperresponsiveness. This model has provided useful information on the mechanisms underlying the pathophysiological events that typify the chronic bronchitis in humans.

Animals↗
PubMed1999

Mouse models of airway responsiveness: physiological basis of observed outcomes and analysis of selected examples using these outcome indicators.

The mouse is an ideal species for investigation at the interface of lung biology and lung function. As detailed in this review, there are well-developed methods for the quantitative study of lung function in mice. These methods can be applied to mice in both terminal and nonterminal experiments. Terminal experimental approaches provide more detailed physiological information, but nonterminal measurements provide adequate data for certain experiments. In this review, we provide two examples of how these models can be used to further understanding of the primary pathobiology of airway responsiveness in both the absence and the presence of induced airway inflammation. The first model is a dissection of chromosomal loci linked to the variance in airway responsiveness observed in the absence of any manipulation to induce airway inflammation. The second model explores the role of T-cell costimulatory signals in the induction of airway hyperresponsiveness. As the number of mice with targeted deletions of effector genes or insertion of informative transgenes grows, additional examples are likely to accrue.

Allergens↗
PubMed1999

Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7 in inbred mice.

Quantitative trait locus (QTL) mapping was used to identify chromosomal regions contributing to airway hyperresponsiveness in mice. Airway responsiveness to methacholine was measured in A/J and C3H/HeJ parental strains as well as in progeny derived from crosses between these strains. QTL mapping of backcross [(A/J x C3H/HeJ) x C3H/HeJ] progeny (n = 137-227 informative mice for markers tested) revealed two significant linkages to loci on chromosomes 6 and 7. The QTL on chromosome 6 confirms the previous report by others of a linkage in this region in the same genetic backgrounds; the second QTL, on chromosome 7, represents a novel locus. In addition, we obtained suggestive evidence for linkage (logarithm of odds ratio = 1.7) on chromosome 17, which lies in the same region previously identified in a cross between A/J and C57BL/6J mice. Airway responsiveness in a cross between A/J and C3H/HeJ mice is under the control of at least two major genetic loci, with evidence for a third locus that has been previously implicated in an A/J and C57BL/6J cross; this indicates that multiple genetic factors control the expression of this phenotype.

Animals↗
PubMed1999

Mast cell activation is not required for induction of airway hyperresponsiveness by ozone in mice.

Exposure to ambient ozone (O3) is associated with increased exacerbations of asthma. We sought to determine whether mast cell degranulation is induced by in vivo exposure to O3 in mice and whether mast cells play an essential role in the development of pulmonary pathophysiological alterations induced by O3. For this we exposed mast cell-deficient WBB6F1-kitW/kitW-v (kitW/kitW-v) mice and the congenic normal WBB6F1 (+/+) mice to air or to 1 or 3 parts/million O3 for 4 h and studied them at different intervals from 4 to 72 h later. We found evidence of O3-induced cutaneous, as well as bronchial, mast cell degranulation. Polymorphonuclear cell influx into the pulmonary parenchyma was observed after exposure to 1 part/milllion O3 only in mice that possessed mast cells. Airway hyperresponsiveness to intravenous methacholine measured in vivo under pentobarbital anesthesia was observed in both kitW/kitW-v and +/+ mice after exposure to O3. Thus, although mast cells are activated in vivo by O3 and participate in O3-induced polymorphonuclear cell infiltration into the pulmonary parenchyma, they do not participate detectably in the development of O3-induced airway hyperresponsiveness in mice.

Animals↗
PubMed1999

Simple tandem repeat polymorphisms in the neuronal nitric oxide synthase gene in different ethnic populations.

Allelic frequencies of a CA dinucleotide repeat in exon 29 and an intronic AAT trinucleotide repeat in the neuronal nitric oxide synthase (NOS1) gene were determined by simple sequence length polymorphism (SSLP) in 305 American-Caucasian and 105 African-American healthy subjects. There were highly significant differences in allele frequencies between the two ethnically diverse study populations.

Alleles↗
PubMed1999

Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma.

Recent family-based studies have revealed evidence for linkage of human chromosome 5q31 to the diagnosis of asthma, elevated serum IgE levels, and bronchial hyperresponsiveness. Among the candidate genes in this region is the gene encoding for human interleukin-4 (IL-4). We reasoned that this gene could also serve as a candidate gene with respect to asthma severity as indicated by the FEV(1) measured when bronchodilator treatment was withheld. To test this hypothesis, we examined a large population of patients with asthma (ascertained without respect to genetic characteristics), for associations between a genetic variant in the IL-4 promoter region (C-589T) and asthma severity, as indicated by FEV(1). We used amplification by the polymerase chain reaction followed by BsmF1 restriction digestion to assign genotypes at the IL-4 promoter C-589T locus. We compared genotypes at this locus in 772 Caucasian and African American patients with asthma of varying severity, and we used multiple regression analysis to relate genotypic findings to FEV(1). Among white individuals, the homozygous presence of the C-589T IL-4 promoter genotype (TT) was associated with a FEV(1) below 50% of predicted (p = 0.013; OR, 1.44; 95% CI: 1.09 to 1.90). Subjects with the TT genotype had mean FEV(1) (% predicted) values 4.5% lower than those of subjects with the wild-type (CC) genotype at this locus. FEV(1) values of white patients with a CC or CT genotype were broadly distributed, whereas the TT genotype was associated with a narrow distribution of low FEV(1) values. The frequency of the T allele was significantly greater (p = 1 x 10(-)(23)) among African American asthmatics (0.544) than among white asthmatics (0.183). These data provide the first evidence associating FEV(1) in patients with asthma and genetic determinants at any locus. Our data are consistent with the idea that the FEV(1) in asthma is the result of multiple factors; one of these factors is the genotype at the IL-4 C-589T locus. This locus is associated with a small but significant decrement in pulmonary function among white asthmatic subjects.

Adult↗
PubMed1999

Eotaxin and impaired lung function in asthma.

We performed an association study of plasma eotaxin levels, eosinophil counts, total IgE levels, asthma diagnosis, and lung function in an ethnically diverse and geographically dispersed population. We studied 515 asthmatic and 519 normal subjects, none of whom was taking inhaled or oral corticosteroids. Logistic regression analysis demonstrated a direct relationship between asthma diagnosis and eotaxin levels (p < 0.0001). The odds of an asthma diagnosis increased with eotaxin quartile, with the highest quartile having an odds ratio of 5.4 (95% CI 3.2 to 9.2, p < 0.001) compared with the lowest eotaxin quartile. Eotaxin levels were inversely related to lung function (p < 0.001), with the mean percent predicted FEV(1) in the highest eotaxin quartile being 13.5 percentage points (SEM 2.1, p < 0.001) less than that in the lowest quartile. Plasma eotaxin levels were associated with asthma and inversely related to lung function independent of age, race, sex, or smoking status. When combined with eosinophil counts and IgE levels, eotaxin levels contributed to the odds of an asthma diagnosis and of impaired lung function. Our results are the first to associate eotaxin levels with asthma diagnosis and compromised lung function in a large geographically and ethnically diverse population.

Adult↗
PubMed1999

Antigen-induced airway hyperresponsiveness, pulmonary eosinophilia, and chemokine expression in B cell-deficient mice.

Murine models of allergen-induced pulmonary inflammation share many features with human asthma, including the development of antigen-induced pulmonary eosinophilia, airway hyperresponsiveness, antigen-specific cellular and antibody responses, the elaboration of Th2 cytokines (interleukin [IL]-4 and IL-5), and the expression of chemokines with activity for eosinophils. We examined the role of B cells and antigen-specific antibody responses in such a model by studying the histopathologic and physiologic responses of B cell-deficient mice compared with wild-type controls, following systemic immunization and airway challenge with ovalbumin (OVA). Both OVA-challenged wild-type and B cell-deficient mice developed (1) airway hyperresponsiveness, (2) pulmonary inflammation with activated T cells and eosinophils, (3) IL-4 and IL-5 secretion into the airway lumen, and (4) increased expression of the eosinophil active chemokines eotaxin and monocyte chemotactic protein-3. There were no significant differences in either the pathologic or physiologic responses in the B cell-deficient mice compared with wild-type mice. These data indicate that B cells and antigen-specific antibodies are not required for the development of airway hyperresponsiveness, eosinophilic pulmonary inflammation, and chemokine expression in sensitized mice following aerosol challenge with antigen.

Animals↗
PubMed1999

Interleukin-8 receptor modulates IgE production and B-cell expansion and trafficking in allergen-induced pulmonary inflammation.

We examined the role of the interleukin-8 (IL-8) receptor in a murine model of allergen-induced pulmonary inflammation using mice with a targeted deletion of the murine IL-8 receptor homologue (IL-8r-/-). Wild-type (Wt) and IL-8r-/- mice were systemically immunized to ovalbumin (OVA) and were exposed with either single or multiple challenge of aerosolized phosphate-buffered saline (OVA/PBS) or OVA (OVA/OVA). Analysis of cells recovered from bronchoalveolar lavage (BAL) revealed a diminished recruitment of neutrophils to the airway lumen after single challenge in IL-8r-/- mice compared with Wt mice, whereas multiply challenged IL-8r-/- mice had increased B cells and fewer neutrophils compared with Wt mice. Both Wt and IL-8r-/- OVA/OVA mice recruited similar numbers of eosinophils to the BAL fluid and exhibited comparable degrees of pulmonary inflammation histologically. Both total and OVA-specific IgE levels were greater in multiply challenged IL-8r-/- OVA/OVA mice than in Wt mice. Both the IL-8r-/- OVA/OVA and OVA/PBS mice were significantly less responsive to methacholine than their respective Wt groups, but both Wt and IL-8r mice showed similar degrees of enhancement after multiple allergen challenge. The data demonstrate that the IL-8r modulates IgE production, airway responsiveness, and the composition of the cells (B cells and neutrophils) recruited to the airway lumen in response to antigen.

Allergens↗
PubMed1999

Bronchodilator responsiveness and serum total IgE levels in families of probands with severe early-onset COPD.

Bronchodilator responsiveness has been associated with a subsequent accelerated decline in forced expiratory volume in one second (FEV1). Therefore, bronchodilator responsiveness and total serum immunoglobulin E(IgE) levels were assessed in 184 adult first-degree relatives of probands with severe early-onset chronic obstructive pulmonary disease (COPD) and a control group. Greater bronchodilator responsiveness was found among current smokers or exsmokers who were first-degree relatives of early-onset COPD probands than in currently or exsmoking controls, expressed as increase in FEV1 as a percentage of baseline (5.8+/-8.1 versus 2.9+/-5.1%, p<0.01), absolute increase in FEV1 from baseline (120+/-130 versus 60+/-110 mL, p<0.05), and increase in FEV1 as a percentage of the predicted value (3.6:4.1 versus 2.2+/-3.9%, p<0.05). However, elevated total serum IgE levels were not found in first-degree relatives of early-onset COPD probands compared with control subjects. The increased bronchodilator responsiveness among currently smoking/exsmoking first-degree relatives of early-onset COPD probands suggests that these individuals may have enhanced susceptibility to the detrimental effects of cigarette smoking.

Adult↗
PubMed1999

Leukotriene modifiers and Churg-Strauss syndrome: adverse effect or response to corticosteroid withdrawal?

Zafirlukast, montelukast and pranlukast are all cysteinyl leukotriene receptor antagonists that have recently been approved for the treatment of asthma. Within 6 months of zafirlukast being made available on the market, 8 patients who received the agent for moderate to severe asthma developed eosinophilia, pulmonary infiltrates, cardiomyopathy and other signs of vasculitis; the syndrome that these patients developed was characteristic of the Churg-Strauss syndrome. All of the patients had discontinued systemic corticosteroid use within 3 months of presentation and all developed the syndrome within 4 months of zafirlukast initiation. The syndrome dramatically improved in each patient upon reinitiation of corticosteroid therapy. Since the initial report, there have been multiple similar cases reported to the relevant pharmaceutical companies and to federal drug regulatory agencies in association with zafirlukast as well as with pranlukast, montelukast, and with use of high doses of inhaled corticosteroids, thus leading to an increased incidence rate of the Churg-Strauss syndrome. Many potential mechanisms for the association between these drugs and the Churg-Strauss syndrome have been postulated including: increased syndrome reporting due to bias; potential for allergic drug reaction; and leukotriene imbalance resulting from leukotriene receptor blockade. However, careful analysis of all reported cases suggests that the Churg-Strauss syndrome develops primarily in those patients taking these asthma medications who had an underlying eosinophilic disorder that was being masked by corticosteroid treatment and unmasked by novel asthma medication-mediated corticosteroid withdrawal, similar to the forme fruste of the Churg-Strauss syndrome. It remains unclear what the exact mechanism for this syndrome is and whether this represents an absolute increase in cases of vasculitis, but it appears that none of the asthma medications implicated in leading to the development of Churg-Strauss syndrome was directly causative of the syndrome. These agents remain well tolerated and effective medications for the treatment of asthma, although physicians must be wary for the signs and symptoms of the Churg-Strauss syndrome, particularly in patients with moderate to severe asthma in whom corticosteroids are tapered.

Acetates↗
PubMed1999

Neuronal NO synthase (NOS1) is a major candidate gene for asthma.

Asthma is a common, but heterogeneous disease, characterized by reversible airway obstruction, bronchial hyperresponsiveness (BHR); and is commonly associated with atopy. The messenger molecule nitric oxide (NO), that is formed by neuronal NO synthase (NOS1), is known to have a key role in bronchomotor control in animals. In humans the gene for NOS1 is located on chromosome 12q24, in a region that had been shown in family studies to be linked to the diagnosis of asthma. We identified variants of the NOS1 gene, and assessed whether there was a genetic association between these variants of NOS1 and the diagnosis asthma. A total of 410 Caucasian asthma patients and 228 Caucasian controls were screened for three bi-allelic polymorphisms in the NOS1 gene that had been detected by single-stranded conformational polymorphism (SSCP) analysis and confirmed by sequencing. Allele frequencies of a polymorphism in exon 29 of the NOS1 gene were significantly different between asthmatics and controls (P<0.05). These findings suggest that variants of the NOS1 gene may be one source of genetic risk for asthma.

Asthma↗