Search PubMed⌕ Search

Biomedical subjects

J M Drazen

Publications and source records attributed to J M Drazen.

At least 145 records · Page 8Linked to original sources
PubMed1995

Expired nitric oxide levels during treatment of acute asthma.

Nitric oxide (NO) is known to be present in measurable quantities in the exhaled air of normal subjects and at higher concentrations in asthmatic subjects not treated with glucocorticoids. We confirmed these findings by analyzing the mean mixed expired NO concentrations of 43 stable asthmatics and 90 normal subjects; NO levels were higher in the asthmatic population (13.9 parts per billion [ppb] versus 6.2 ppb, p < 0.001). Although the effects of glucocorticoids on the NO content of mixed expired air are known, it is not known if beginning systemic glucocorticoid therapy reduces exhaled NO levels in a given individual. To examine this question, seven patients needing emergency therapy for asthma underwent repeated measurements of mixed expired NO levels during their course of treatment with glucocorticoids. All patients had a reduction in mixed expired NO concentration (p = 0.002) and an accompanying improvement in airway obstruction. The decrease in exhaled NO was evident as early as 48 h after the initiation of therapy (p = 0.05). These data suggest mixed expired NO concentrations may prove useful as an index of asthma severity and treatment efficacy for an individual patient.

Acute Disease↗
PubMed1995

Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects.

The leukotrienes are known bronchoactive agonists with potential proinflammatory effects that may be involved in mediating airway hyperresponsiveness. We investigated the effects of zileuton, an inhibitor of 5-lipoxygenase (5-LO), on airway responsiveness to cold, dry air in patients with moderate asthma. A group of 10 asthmatic patients underwent cold, dry air hyperventilation challenge; challenges were performed before drug treatment and 1 to 10 d after the completion of treatment with study drugs. The cold air minute ventilation required to cause a 15% decrease in FEV1 (PD15 VE) increased by 58% compared with the response before treatment, 1 to 10 d after the completion of 13 wk of treatment with zileuton. The geometric mean (geometric mean/SEM and geometric mean x SEM) PD15 VE increased from 24.5 (20.4, 29.5) L/min to 38.8 (34.7, 43.7) L/min (p = 0.01). Zileuton treatment inhibited 5-LO as measured ex vivo by ionophore-stimulated LTB4 levels in whole blood. In four of seven subjects, LTB4 levels before zileuton ingestion fell from 110.88 +/- 25.42 to 5.40 +/- 1.95 ng/ml 2 h post-zileuton dosing (p = 0.02, pre- versus 2 h postzileuton ingestion). Consistent with the short half-life of zileuton, 6 h postzileuton dosing the ionophore-stimulated, LTB4 levels in whole blood had increased to 89.68 +/- 35.54 ng/ml (p = 0.41, pre- versus 6 h postzileuton ingestion). Based on the first-order kinetics of zileuton, its effect on 5-LO activity should have been dissipated less than 16 h postingestion. Thus, chronic zileuton treatment decreased airway hyperresponsiveness as determined by reactivity to cold, dry air.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Airway wall liquid. Sources and role as an amplifier of bronchoconstriction.

Airway liquid balance in asthma is largely determined by active plasma exudation from tracheobronchial microvessels into the interstitial spaces of the mucosa, submucosa, and/or adventitia, and from there into the luminal space. This exuded plasma is rich in proteins and cell mediators capable of initiating several events, including activation of sensory neural pathways, plasma protein cleavage, inflammatory cell recruitment, and inhibition of surfactant function. It can act to amplify the bronchoconstrictor response by increasing mucosal and/or submucosal thickness, altering mechanical properties of airway wall compartments, decoupling the airway wall from parenchymal attachments, filling airway interstices, and by creating an additional inward force because of surface tension, resulting in further airway constriction and possibly closure and thereby significantly increasing airways resistance.

Animals↗
PubMed1994

Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells.

Histochemical activity and immunoreactivity of nitric oxide synthase (NOS, EC 1.14.13.39) have been recently demonstrated in human lung epithelium. However, the molecular nature of NOS and the regulation and function of the enzyme(s) in the airway is not known. A549 cells (human alveolar type II epithelium-like), BEAS 2B cells (transformed human bronchial epithelial cells), and primary cultures of human bronchial epithelial cells all exhibited constitutive NOS activity that was calcium dependent and inhibitable by the NOS inhibitor NG-monomethyl-L-arginine. Nitric oxide production by epithelial cells was enhanced by culture in the presence of interferon gamma, interleukin 1 beta, tumor necrosis factor alpha, and lipopolysaccharide; the NOS activity expressed under these conditions showed less dependence on calcium, reminiscent of other inducible forms of NOS. Two distinct NOS mRNA species, homologous to previously identified constitutive brain (type I) and inducible hepatic (type II) NOS, were demonstrated by reverse transcription-polymerase chain reaction in all cell lines. Northern analysis confirmed the expression of inducible NOS mRNA. Cell culture with epidermal growth factor, a principal regulator of epithelial cell function, decreased inducible NOS activity by posttranscriptional action but did not affect constitutive NOS activity. The coexistence of constitutive and inducible NOS in human alveolar and bronchial epithelial cells is consistent with a complex mechanism evolved by epithelial cells to protect the host from microbial assault at the air/surface interface while shielding the host from the induction of airway hyperreactivity.

Adenocarcinoma↗
PubMed1994

Active anaphylaxis in IgE-deficient mice.

The IgE-triggered release of mast cell mediators in response to antigen is thought to be the primary event in immediate hypersensitivity reactions such as systemic anaphylaxis. Although mast cells and basophils can be activated in vitro by non-IgE stimuli, it is not known whether these triggers lead to physiological changes in vivo. To investigate this possibility, we generated mice with a homozygous null mutation of the C epsilon gene. Such mice make no IgE, but produce other immunoglobulin isotypes normally. We report that despite the IgE deficiency, sensitized mutant mice become anaphylactic on antigen challenge and display tachycardia and pulmonary function changes similar to those seen in wild-type animals. These responses are accompanied by vascular leak, sharply elevated plasma histamine and rapid death. IgE-independent anaphylaxis does not depend on complement activation, but, as indicated in studies using genetically immunodeficient RAG-2- and SCID mice, does require a functional immune system. Such results clearly demonstrate that non-IgE pathways for hypersensitivity reactions exist in mice.

Anaphylaxis↗
PubMed1994

Reduction in viscosity of cystic fibrosis sputum in vitro by gelsolin.

Obstruction of airways by viscous sputum causes lung damage in patients with cystic fibrosis (CF). Sputum samples from CF patients were shown to contain filamentous actin. Human plasma gelsolin, a protein that severs actin filaments, rapidly decreased the viscosity of CF sputum samples in vitro. Gc globulin and deoxyribonuclease I, proteins that sequester monomeric actin but do not sever actin filaments, were less efficient than gelsolin in diminishing sputum viscosity. These results suggest that gelsolin may have therapeutic potential as a mucolytic agent in CF patients.

Actins↗
PubMed1994

Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma.

BACKGROUND: A subset of patients with asthma experience adverse nasoocular reactions after ingestion of aspirin or agents that inhibit cyclooxygenase. Recent evidence has implicated the leukotrienes in the nasoocular reaction, but the cellular sources and mechanism of activation are unknown. We used nasal lavage with and without a 5-lipoxygenase inhibitor, zileuton, to define the role of leukotrienes and to profile nasal cellular activation during this reaction. METHODS: A group of eight patients with asthma shown to have adverse reactions to aspirin documented by a 15% or greater decrease in forced expiratory volume in 1 second, accompanied by an elevation in urinary leukotriene E4 after ingestion of aspirin, received aspirin or placebo in a study with a crossover design. Nasal symptoms and nasal tryptase, histamine, leukotriene, and eosinophil cationic protein levels were evaluated. Serum tryptase and urinary histamine levels were also assessed. Subjects were then randomized to receive a week of treatment with zileuton or placebo, according to a double-blind, crossover design followed by aspirin challenge and measurement of the same mediators. RESULTS: Aspirin ingestion produced a marked increase in nasal symptoms from a baseline symptom score of 2.1 +/- 0.7 to a maximum of 8.4 +/- 1.2 (p < 0.0007). Aspirin ingestion produced a mean maximal increase in nasal tryptase of 3.5 +/- 2.6 ng/ml, whereas placebo ingestion produced a mean maximal increase of 0.1 +/- 0.2 ng/ml (p < 0.05, aspirin vs placebo). Mean maximal nasal histamine increased 1.73 +/- 1.16 ng/ml versus 0.08 +/- 0.08 ng/ml from baseline (p < 0.05, aspirin vs placebo). Aspirin produced a mean maximal increase in nasal leukotriene value of 152 pg/ml versus a 16 pg/ml decrease after placebo ingestion (p < 0.05). Zileuton treatment blocked the increase in nasal symptoms after aspirin ingestion (maximum nasal symptom score of 1.6 +/- 0.6 with zileuton vs 5.5 +/- 0.9 with placebo [p < 0.0053]). It also blocked the rise in nasal tryptase (p = 0.011) and nasal leukotriene (p < 0.05) levels after aspirin ingestion. Zileuton treatment had no significant effect on the recovery of nasal histamine. CONCLUSION: The increase in nasal symptoms in aspirin-sensitive patients with asthma after aspirin ingestion is associated with increases in nasal tryptase, histamine, and cysteinyl leukotriene levels. This mediator profile is consistent with mast cell activation during the nasal response to aspirin and suggests that 5-lipoxygenase products are essential for the nasal response to aspirin.

Adult↗
PubMed1994

Airway surface liquid thickness as a function of lung volume in small airways of the guinea pig.

The average thickness and distribution of airway surface liquid (ASL) on the luminal surface of peripheral airways were measured in normal guinea pig lungs frozen at functional residual capacity (FRC) and total lung capacity (TLC). Tissue blocks containing cross sections of airways of internal perimeter 0.188-3.342 mm were cut from frozen lungs and imaged by low-temperature scanning electron microscopy (LTSEM). Measurements made from LTSEM images were found to be independent of freezing rate by comparison of measurements at rapid and slow freezing rates. At both lung volumes, the ASL was not uniformly distributed in either the circumferential or longitudinal direction; there were regions of ASL where its thickness was < 0.1 micron, whereas in other regions ASL collected in pools. Discernible liquid on the surfaces of airways frozen at FRC followed the contours of epithelial cells and collected in pockets formed by neighboring cells, a geometry consistent with a low value of surface tension at the air-liquid interface. At TLC airway liquid collected to cover epithelial cells and to form a liquid meniscus, a geometry consistent with a higher value of surface tension. The average ASL thickness (h) was approximately proportional to the square root of airway internal perimeter, regardless of lung volume. For airways of internal perimeter 250 and 1,800 microns, h was 0.9 and 1.8 microns at FRC and 1.7 and 3.7 microns at TLC, respectively. For a given airway internal perimeter, h was 1.99 times thicker at TLC than at FRC; the difference was statistically significant (P < 0.01; 95% confidence interval 1.29-3.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The biology of nitrogen oxides in the airways.

Nitrogen oxides (NOx), regarded in the past primarily as toxic air pollutants, have recently been shown to be bioactive species formed endogenously in the human lung. The relationship between the toxicities and the bioactivities of NOx must be understood in the context of their chemical interactions in the pulmonary microenvironment. Nitric oxide synthase (NOS) is a newly identified enzyme system active in airway epithelial cells, macrophages, neutrophils, mast cells, autonomic neurons, smooth muscle cells, fibroblasts, and endothelial cells. The chemical products of NOS in the lung vary with disease states, and are involved in pulmonary neurotransmission, host defense, and airway and vascular smooth muscle relaxation. Further, certain patients with pulmonary hypertension, adult respiratory distress syndrome and asthma may experience physiologic improvement with NOx therapy, including inhalation of nitric oxide (NO.) gas. Both endogenous and exogenous NOx react readily with oxygen, superoxide, water, nucleotides, metalloproteins, thiols, amines, and lipids to form products with biochemical actions ranging from bronchodilation and bacteriostasis (S-nitrosothiols) to cytotoxicity and pulmonary capillary leak (peroxynitrite), as well as those with frank mutagenic potential (nitrosamines). Recent discoveries demonstrating the relevance of these species to the lung have provided new insights into the pathophysiology of pulmonary disease, and they have opened a new horizon of therapeutic possibilities for pulmonary medicine.

Amino Acid Oxidoreductases↗
PubMed1994

Capsaicin-induced airway obstruction in tracheally perfused guinea pig lungs.

The neurokinin receptors responsible for transducing the airway obstruction resulting from capsaicin infusion were defined in the tracheally perfused guinea pig lung. In this lung preparation, buffer is perfused via the trachea and allowed to exit the lung through numerous small holes in the pleural surface; airway obstruction is monitored as the backpressure (Pao) generated at a constant perfusion flow rate. Infusion of the specific NK1 receptor agonist, Sar-9 Met02(11) substance P, resulted in an increase in Pao; this effect was prevented by the NK1 receptor antagonist CP 99,994 but not by the NK2 receptor antagonist SR 48,968. Infusion of the specific NK2 receptor agonist Nle10-neurokinin A 4-10 resulted in an increase in Pao; this effect was prevented by the NK2 receptor antagonist SR 48,968 but not by the NK1 receptor antagonist CP 99,994. In the absence of NK receptor antagonists, infusion of capsaicin resulted in a significant increase in Pao, 31 +/- 4 cm H2O. In the presence of the NK1 receptor antagonist, the capsaicin response was not diminished, but in the presence of the NK2 receptor antagonist, the Pao response diminished to only 10 +/- 2 cm H2O, p < 0.001. These data indicate that when capsaicin is presented to the epithelial surface of the lung the resulting airway obstruction is mediated predominantly by NK2 receptor stimulation.

Animals↗
PubMed1994

The influence of age, diagnosis, and gender on proper use of metered-dose inhalers.

Metered dose inhalers (MDIs) are widely used in clinical practice for administering pharmaceuticals targeted to the lung. It is well known that the inhalation technique used with MDIs can substantially influence the clinical response to inhaled medications. To determine the acceptability of MDI maneuvers, we studied 59 subjects (26 females and 33 males; age, 20 to 81 yr; mean age, 38 yr) to determine whether the MDI technique used by these individuals complied with published recommendations for acceptable inhalation technique. Measurements were made with an MDI adapter that contained an unobtrusive, lightweight, miniature sensing system. Inspiratory flow at the moment of MDI actuation (Va), the volume (integrated from airflow) at actuation as a fraction of total inspiratory volume (Va/VI), breath-holding time (tBH), and inspiratory volume as a fraction of FVC (VI/FVC) were determined from 59 uncoached inhalations. We defined an acceptable maneuver, based on published data, by four components: (1) inspiratory flow at actuation (Va) between 25 and 90 L/min; (2) actuation during early inspiration (0 < Va/VI < or = 0.20); (3) adequate breath-holding time (tBH > 4 s), and (4) a deep inhalation (VI/FVC > 0.50). For all subjects, only 25% of inhalation maneuvers met all four criteria for acceptability. We found that a significantly higher proportion of male than female subjects performed an acceptable MDI maneuver (43% versus 4%, p < 0.001). There were no significant differences in technique between younger and older subjects or between patients with a diagnosis of asthma or chronic obstructive pulmonary disease (COPD). We conclude that most patients use their MDIs incorrectly; females of all ages are much more likely to have improper MDI technique than are males.

Adult↗
PubMed1994

Effects of chronic airway inflammation on the activity and enzymatic inactivation of neuropeptides in guinea pig lungs.

The effects of airway inflammation induced by chronic antigen exposure on substance P (SP)-induced increases and vasoactive intestinal peptide (VIP)-induced decreases in airway opening pressure (Pao), and the recovery of intact and hydrolyzed radiopeptide were studied in tracheally perfused guinea pig lungs. SP (10(-6) mol/kg) induced a significantly greater increase in Pao in lungs from antigen-exposed (30 +/- 5 cm H2O) than saline-exposed animals (15 +/- 1 cm H2O, P < 0.05). Significantly more intact 3H-SP and significantly less 3H-SP 1-7, a neutral endopeptidase (NEP) hydrolysis product, were recovered from the lung effluent of antigen-exposed than saline-exposed animals (P < 0.05). Injection of VIP (10(-9) mol/kg) induced significantly more pulmonary relaxation in saline-exposed compared with antigen-exposed lungs (62 +/- 4%, P < 0.001). In contrast to effluent from saline-exposed animals, lung effluent from antigen-exposed lungs contained less intact VIP, increased amounts of a tryptic hydrolysis product, and no products consistent with the degradation of VIP by NEP. These data indicate that inflamed lungs are more sensitive to the contractile effects of SP because it is less efficiently degraded by NEP and are less sensitive to the relaxant effects of VIP because it is more efficiently degraded by a tryptic enzyme. Changes in airway protease activity occur with allergic inflammation and may contribute to airway hyperresponsiveness.

Animals↗
PubMed1994

Relaxation of human bronchial smooth muscle by S-nitrosothiols in vitro.

S-Nitrosothiols (RS-NO) relax tracheal smooth muscle from a variety of animal species, and may have physiological relevance. We therefore studied their effects on human bronchial smooth muscle. S-Nitroso adducts of glutathione, cysteine, N-acetylcysteine and bovine serum albumin relaxed tissues contracted with methacholine with mean IC50 +/- S.E.M. of 3.3 (+/- 14), 22 (+/- 45), 25 (+/- 22) and 36 (+/- 7.1) microM, respectively; they were more potent as inhibitory agonists than the corresponding reduced thiol, NaNO2, or theophylline, but less potent than isoproterenol (P < .001). Despite large differences in their molecular weights and dissociation kinetics, the IC50 of these RS-NO did not differ significantly from one another, from nitric oxide (NO.) or from sodium nitroprusside. Consistent with the role of cyclic GMP (cGMP) in mediating relaxation responses, S-nitroso-N-acetyl cysteine (S-NO-AC) (100 microM) increased tissue cGMP levels 4-fold, and 8-bromo-cGMP caused modest tissue relaxation which was potentiated by the phosphodiesterase inhibitor, dipyridamole (1 microM). However, the guanylyl cyclase inhibitors, methylene blue (100 microM) and LY 83583 (50 microM), failed to modify the relaxation response to S-NO-AC (sodium nitroprusside and NO.), while altering the accumulation of cGMP. Further, hemoglobin (100 microM) failed to inhibit relaxation by S-NO-AC.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchi↗
PubMed1994

Serotonin-induced pulmonary responses are mediated by the 5-HT2 receptor in the mouse.

C57BL/6 mice exhibit acute transient decreases in lung conductance (GL) and dynamic compliance (Cdyn) after intravenous administration of serotonin (5-HT). To identify the specific agonist receptor subtypes responsible for this bronchoconstriction, we measured changes in pulmonary function in C57BL/6 mice in response to intravenous infusion of 5-HT receptor subtype-selective agonists and to 5-HT in the presence of antagonists selective for the 5-HT2 or 5-HT3 receptor subtypes. Agonists selective for the 5-HT1A/1B/1D or 5-HT3 receptor subtypes induced minimal or undetectable pulmonary responses, whereas infusion of alpha-methyl-5-hydroxytryptamine, a 5-HT2 receptor-selective agonist, led to dose-related decreases in Cdyn and GL. The selective 5-HT3 receptor antagonist, LY278584 maleate, (1.0 mg/kg i.v.) caused no detectable reduction in the response to 100 micrograms/kg of 5-HT. In contrast, treatment with the 5-HT2 receptor antagonist LY53857 (10 micrograms/kg i.v.) resulted in a significant diminution of the pulmonary response observed after infusion of 100 micrograms/kg of 5-HT. Dose-response relationships were established for 5-HT in experiments in which each mouse was treated with a single dose of 5-HT without antagonist or after LY53857. Compared with responses to doses of 5-HT of more than 100 micrograms/kg in the absence of antagonist, pulmonary responses to 5-HT after infusion of 10 micrograms/kg of LY53857 were significantly reduced; 100 micrograms/kg of LY53857 nearly abolished the responses to all doses of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways.

Recent discoveries suggesting essential bioactivities of nitric oxide (NO.) in the lung are difficult to reconcile with the established pulmonary cytotoxicity of this common air pollutant. These conflicting observations suggest that metabolic intermediaries may exist in the lung to modulate the bioactivity and toxicity of NO.. We report that S-nitrosothiols (RS-NO), predominantly the adduct with glutathione, are present at nano- to micromolar concentrations in the airways of normal subjects and that their levels vary in different human pathophysiologic states. These endogenous RS-NO are long-lived, potent relaxants of human airways under physiological O2 concentrations. Moreover, RS-NO form in high concentrations upon administration of NO. gas. Nitrite (10-20 microM) is found in airway lining fluid in concentrations linearly proportional to leukocyte counts, suggestive of local NO. metabolism. NO. itself was not detected either free in solution or in complexes with transition metals. These observations may provide insight into the means by which NO. is packaged in biological systems to preserve its bioactivity and limit its potential O2-dependent toxicity and suggest an important role for NO. in regulation of airway luminal homeostasis.

Adolescent↗