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Biomedical subjects

J M Drazen

Publications and source records attributed to J M Drazen.

At least 217 records · Page 12Linked to original sources
PubMed1988

Substance P-induced bronchoconstriction in the guinea pig. Enhancement by inhibitors of neutral metalloendopeptidase and angiotensin-converting enzyme.

We tested the effects of the neutral metalloendopeptidase (NEP) inhibitor, thiorphan (0.17, 0.5, and 1.7 mg i.v), and the angiotensin-converting enzyme (ACE) inhibitor, captopril (0.5, 1.7, and 5.0 mg i.v.), on the bronchoconstrictor response to rapid intravenous infusions of substance P (0.1 to 30 nmol/kg) in anesthetized, mechanically ventilated guinea pigs. The decreases in pulmonary conductance and dynamic compliance caused by substance P were greater in animals treated with either thiorphan or captopril than in control animals. Thiorphan (0.5 mg) had no effect on airway responsiveness to intravenously administered methacholine, whereas captopril (1.7 mg) caused a small increase in methacholine responsiveness. Both drugs significantly increased the recovery of immunoreactive substance P in arterial plasma after exogenous administration of the peptide. We conclude that degradation of substance P by both NEP and ACE is important for determining the magnitude of the bronchoconstriction caused by intravenous administration of this neuropeptide. These data suggest that conditions associated with diminished peptidase activity could result in enhanced responses to stimuli which cause the release of endogenous substance P.

Amino Acids, Sulfur↗
PubMed1988

Synergism between inflammatory mediators in vivo. Induction of airway hyperresponsiveness to C3a in the guinea pig.

The complement anaphylatoxin C3a causes acute bronchoconstriction after intravenous infusion in guinea pigs. At doses of 6 to 600 micrograms/kg, the peptide causes significant and dose-dependent increases in resistance (RL) and decreases in dynamic compliance (Cdyn). Inhibition of serum carboxypeptidase N, the enzyme thought to be responsible for control of C3a activity in blood, by pretreating animals with DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGPA), resulted in a 4-fold potentiation of the response to 200 micrograms/kg C3a. Responses to lower C3a doses were not significantly affected. Pretreating animals intravenously with histamine prior to administration of C3a resulted in potentiation of C3a-induced bronchoconstriction at all doses tested, decreasing the amount of C3a required to double RL by 15-fold, from 110 to 7 micrograms/kg. The effect appears to be relatively specific for C3a since histamine pretreatment did not alter airway responsiveness to methacholine. Similarly, pretreatment with methacholine at a dose that caused an increase in RL comparable to histamine did not alter subsequent responses to C3a. Administration of capsaicin, under conditions that elicit acute release of endogenous substance P, also resulted in potentiation of C3a responses, to an extent similar to that observed for histamine. These data are consistent with an increase in pulmonary vascular permeability facilitating accessibility of C3a for its receptor to cause bronchoconstriction before it is inactivated by serum carboxypeptidase N. Further, when C3a is generated in the presence of histamine-and/or substance-P-releasing agents, it may be responsible for a greater fraction of altered pulmonary mechanics than has previously been appreciated.

Airway Resistance↗
PubMed1988

Dissociation of temperature-gradient and evaporative heat loss during cold gas hyperventilation in cold-induced asthma.

We examined temperature-gradient and evaporative energy losses during cold gas inhalation challenges in patients with exercise-induced asthma by using gases with similar water-carrying capacities but significantly different volume heat capacities. Seven subjects were asked to hyperventilate mixtures of 80% helium/20% oxygen (HeO2) or 80% sulfur hexafluoride/20% oxygen (SF6O2) for 5 min at a fixed target minute ventilation of 20 x FEV1 and an inspired gas temperature of 0 degrees C. Each subject equilibrated his or her lungs with the appropriate gas mixture prior to testing: PETCO2 and FIO2 were monitored and maintained at constant values (CO2 = 0.05; O2 = 0.20) by CO2 scrubbing and addition of compressed gas to the system. Gas composition, inspired and expired flow rates, and gas temperatures at the airway opening were recorded in real time using a computer-based data collection system that calculated respiratory heat loss on a per breath basis. Bronchoconstriction was quantitated using specific airway conductance measured before and serially after each challenge. The degree of bronchoconstriction correlated closely with evaporative respiratory heat loss (r = 0.658 p less than 0.05), but poorly with both temperature-gradient (r = 0.114, p greater than 0.20) and total (r = 0.268, p greater than 0.15) heat loss. These findings suggest that total respiratory heat loss is not the primary stimulus in exercise-induced asthma, and further suggest that total water loss, or focal heat/water loss, may be important in inducing bronchospasm in this subset of asthmatics.

Adult↗
PubMed1988

Heterogeneity of leukotriene C4 production by eosinophils from asthmatic and from normal subjects.

We evaluated the formation of leukotriene C4 (LTC4) by peripheral blood eosinophils of different densities obtained from asthmatic and normal subjects. When stimulated with 1 microgram/ml of the calcium ionophore A23187 for 15 min at 37 degrees C, eosinophils with densities greater than 1.093 g/ml from asthmatic and normal subjects released 19.1 +/- 4.2 ng LTC4/10(6) eosinophils and 23.9 +/- 5.0 ng LTC4/10(6) eosinophils, respectively. In contrast, lower density eosinophils (densities 1.093 g/ml or less) isolated from the asthmatic subjects released significantly less LTC4 than did eosinophils of similar densities from normal subjects (41.6 +/- 3.0 versus 79.0 +/- 6.7 ng LTC4/10(6) eosinophils, p less than 0.05). Differences could not be demonstrated between the two subject groups in LTC4 metabolism, time course of extracellular release of LTC4, or dose response to A23187, nor were interactions between eosinophils and neutrophils with regard to LTC4 release evident. Thus, hypodense eosinophils elaborate greater quantities of LTC4 than do eosinophils of normal density whether obtained from normal or asthmatic subjects. However, the finding that peripheral blood eosinophils from asthmatic subjects have decreased capacity for the synthesis of LTC4 compared with cells of similar densities isolated from normal subjects demonstrates that the capacity of eosinophils to produce LTC4 is regulated by factors that are not necessarily reflected in the cell density.

Asthma↗
PubMed1988

Transition from normal to hypersecretory bronchial mucus in a canine model of bronchitis: changes in yield and composition.

Density-gradient analysis was used to follow the transition from normal to hypersecretory bronchial mucus in a model of bronchitis induced in dogs by chronic exposure to SO2 gas. Aspirates of saline bronchial lavage were obtained by fiberoptic bronchoscopy from dogs before, during a 6- to 9-month exposure period to SO2 gas, and during a recovery period of similar duration. Prior to SO2 exposure, aspirates from all animals had a low yield of nondialyzable macromolecules (15 +/- 6 mg/aspirate) and similar composition. Specifically, epithelial glycoprotein of typical buoyant density was not detected; rather a glycoconjugate of higher buoyant density with features of both proteoglycan and glycoprotein was identified. Neutral lipids were predominant with lesser amounts of phospholipids; no glycolipids were detected. During the SO2 exposure period, aspirates from five of the eight dogs contained components similar in buoyant density to human bronchitic glycoprotein. Glycoprotein isolated from the canine aspirates was similar to glycoprotein isolated from human chronic bronchitic sputum, having the same carbohydrate composition and range of oligosaccharide size. Further, during and after SO2 exposure some aspirates contained appreciable amounts of glycolipids. These data demonstrate substantial similarities in composition between normal human and canine mucus and in mucus isolated from dogs with chronic airway inflammation induced by repeated irritant exposure and from human patients with chronic bronchitis.

Animals↗
PubMed1987

Longitudinal elastic wave propagation in pulmonary parenchyma.

Consideration of the lung as an elastic continuum led us to investigate the possible propagation of elastic waves. Here the relevant stiffness and density are given by the Lamé constants and density of the parenchyma. To test this hypothesis, we measured propagation velocities (c) in dog lobes by recording transit times of a velocity impulse on one side of the lobe and the subsequent arrival on the other side. We compared our measured values of c with elastic longitudinal wave velocities (c long) predicted by values of elastic moduli given by Lai-Fook et al. (J. Appl. Physiol. 40: 508-513, 1976) as a function of translobar pressure (PL) and our measured densities. Good agreement was found between c and c long. Typical values of c ranged from 250-1,500 cm/s as PL ranged from 2-20 cmH2O. No systematic difference in the c-c long relation was found between inflation and deflation, suggesting that the elastic moduli of lungs are essentially a function of pressure. No significant effect was observed by changing the physical properties of the gas within the lobe [air vs. He vs. sulfur hexafluoride (SF6)], suggesting that indeed we were observing waves associated with the coupling of parenchymal density to parenchymal stiffness.

Animals↗
PubMed1987

Interdependent regional lung emptying during forced expiration: a transistor model.

We recognized similarities between isovolume pressure-flow curves of the lung and emitter-collector voltage-current characteristics of bipolar transistors, and used this analogy to model expiratory flow limitation in a two-generation branching network with parallel nonhomogeneity. In this model, each of two bronchi empty parenchymal compliances through a common trachea, and each branch includes resistances upstream and downstream of a flow-limiting site. Properties of each airway are specified independently, allowing simulation of differences between the tracheal and bronchial generations and between the parallel bronchial paths. Simulations of four types of parallel asymmetry were performed: unilateral peripheral bronchoconstriction; unilateral central bronchoconstriction; asymmetric redistribution of parenchymal compliance; and unilateral alteration of the bronchial area-transmural pressure characteristic. Our results indicate that multiple axial choke points can exist simultaneously in a symmetric lung when large airway opening-pleural pressure gradients exist; despite severe nonhomogeneity of regional lung emptying, flow interdependence among parallel branches tends to maintain a near normal configuration of the overall maximal expiratory flow-volume (MEFV) curve throughout a large fraction of the vital capacity; and sudden changes of slope of the MEFV curve ("knees" or "bumps") may reflect choking in one branch in a nonuniform lung, but need not be obvious even when severe heterogeneity of lung emptying exists.

Airway Resistance↗
PubMed1987

Large-volume ventilation results in bronchoconstriction of Basenji-Greyhound dogs.

We compared the effects of large-volume ventilation on airway responses to aerosolized histamine in anesthetized mongrel dogs with its effects in Basenji-Greyhound crossbred (B-G) dogs. Before bronchoconstriction, large inflations resulted in only small changes of dynamic compliance (Cdyn) and pulmonary resistance (RL) in both groups of dogs. After the induction of a moderate degree of bronchoconstriction with aerosolized histamine, large inflations had a more substantial effect; Cdyn increased by 7.5 +/- 2.3% (mean +/- SE; P less than 0.05), and RL decreased by 32 +/- 3.4% (P less than 0.001) in the mongrel dogs. In the B-G group, Cdyn increased by only 0.2 +/- 1.8% (NS), and RL increased by 29.3 +/- 9.2% (P less than 0.05); these changes differed significantly (P less than 0.05) from those observed in the mongrel dogs. Large-volume ventilation following the administration of indomethacin (10 mg/kg iv) and histamine increased Cdyn by 11.4 +/- 1.8% (NS vs. without indomethacin) and decreased RL by 43.9 +/- 3.4% (P less than 0.05) in the mongrel group. In the B-G group large-volume ventilation increased Cdyn by 7.6 +/- 1.7% (P less than 0.01) and decreased RL by 15.7 +/- 8.1% (P less than 0.05). Thus indomethacin enhanced the bronchodilator effects of large-volume ventilation in mongrel dogs and reversed the bronchoconstrictor effect of this maneuver on RL in B-G dogs.

Animals↗
PubMed1987

Indirect assessment of mucosal surface temperatures in the airways: theory and tests.

We developed and tested a method, based on conduction heat transfer analysis, to infer airway mucosal temperatures from airstream temperature-time profiles during breath-hold maneuvers. The method assumes that radial conduction of heat from the mucosal wall to inspired air dominates heat exchange during a breath-hold maneuver and uses a simplified conservation of energy analysis to extrapolate wall temperatures from air temperature vs. time profiles. Validation studies were performed by simultaneously measuring air and wall temperatures by use of a retractable basket probe in the upper airways of human volunteers and intrathoracic airways of paralyzed intubated dogs during breath holding. In both protocols, a good correlation was demonstrated between directly measured wall temperatures and those calculated from adjacent airstream temperature vs. time profiles during a breath hold. We then calculated intrathoracic bronchial wall temperatures from breath-hold airstream temperature-time profiles recorded in normal human subjects after cold air hyperpnea at 30 and 80 l/min. The calculations show airway wall temperatures in the upper intrathoracic airways that are below core body temperature during hyperpnea of frigid air and upper thoracic airways that are cooler than more peripheral airways. The data suggest that the magnitude of local intrathoracic heat/water flux is not represented by heat/water loss measurements at the airway opening. Both the magnitude and locus of heat transport during cold gas hyperventilation vary with changes in inspired gas temperature and minute ventilation; both may be important determinants of airway responses.

Animals↗
PubMed1987

A formyl peptide contracts guinea pig lung: role of arachidonic acid metabolites.

We studied the role of cyclooxygenase and lipoxygenase products of arachidonic acid metabolism in mediating N-formyl-methionyl-leucyl-phenylalanine- (FMLP) induced contractions of guinea pig lung parenchymal strips. The cyclooxygenase inhibitors indomethacin (10(-5) M) and aspirin (3 X 10(-5) to 10(-4) M), the lipoxygenase inhibitor nordihydroguaiaretic acid (10(-5) to 3 X 10(-5) M), and the combined cyclooxygenase/lipoxygenase inhibitors 1-phenyl-3-pyrazolidinone (Phenidone) (3 X 10(-5) to 3 X 10(-4) M) and BW 755C (10(-5) to 10(-4) M) each caused a decrease in the maximum force induced by FMLP (Fmax) and an increase in the concentration of FMLP required to produce 50% of Fmax (EC50). The thromboxane synthesis inhibitor imidazole (3 X 10(-3) M) also decreased Fmax. The leukotriene D4 receptor antagonist FPL 55712 (5.7 X 10(-6) to 1.9 X 10(-5) M) increased the EC50 for FMLP, whereas desensitization of lung parenchymal strips to leukotriene B4 by pretreatment with this leukotriene (10(-7) M) had no effect on FMLP-induced contraction. After exposure to FMLP (10(-6) M), guinea pig lung produced (as determined by high-performance liquid chromatography and radioimmunoassay) leukotrienes C4 and B4, thromboxane A2 (as measured by its stable degradation product thromboxane B2), and prostaglandin F2 alpha. Lung strips not exposed to FMLP showed no evidence of leukotriene production. We conclude that thromboxane A2 and leukotriene C4 generated in response to FMLP mediate a substantial fraction of the force induced by this peptide in guinea pig lung parenchymal strips.

Acetophenones↗
PubMed1987

In vivo bronchodilator activity of nifedipine in the guinea pig.

We administered histamine subcutaneously to anesthetized guinea pigs to induce prolonged bronchoconstriction and then tested the effect of intravenously administered nifedipine on pulmonary resistance (RL) and dynamic compliance (Cdyn). One mg of subcutaneously administered histamine caused RL to increase by an average of more than 250% and Cdyn to fall on average to 26% of baseline; mean RL remained more than twice baseline, and mean Cdyn remained less than half baseline for 80 min. Intravenously administered nifedipine 3 micrograms/kg and ethanol (diluent) administered 25 min after histamine had no effect on RL but caused a slightly greater fall in Cdyn than in the control animals treated with histamine alone. Nifedipine 30 micrograms/kg, however, exhibited significant bronchodilator activity: 35 min after nifedipine 30 micrograms/kg, RL decreased on average to 41 +/- 17% above baseline (p less than 0.02), and Cdyn increased to 49 +/- 5% below baseline (p less than 0.0001). By comparison, isoproterenol (0.3 to 3.0 micrograms/kg) caused bronchodilation of more rapid onset (within 1 min) and shorter duration of action (approximately 10 min). Thus, we were able to demonstrate bronchodilator activity of nifedipine in vivo, as had been predicted by in vitro studies of guinea pig and human tracheal strips. These results would appear to justify continued exploration of the potential role for calcium channel blockers in the treatment of obstructive lung disease.

Airway Resistance↗
PubMed1987

Bronchoconstrictor effects of leukotriene E4 in normal and asthmatic subjects.

The bronchoconstrictor activity of an aerosol of leukotriene E4(LTE4) was compared with that of histamine in 5 normal and in 6 asthmatic subjects to define the relative potency of LTE4 between the groups using 3 indices of airway response. The FEV1 and the flow rate measured at 30% of vital capacity from partial and maximal expiratory maneuvers (V30-P and V30-M) were measured. The geometric mean (GSEM) concentration of LTE4 required to reduce the V30-P by 30% was 0.30 (1.46) mM in the normal subjects, and 0.058 (1.63) in the asthmatic subjects; LTE4 was 39-fold more potent than histamine in the former and 14-fold in the latter group. Further, we observed that when normal and asthmatic subjects were compared at a degree of bronchoconstriction resulting in a 30% decrement in the V30-P after inhaling LTE4, there was a greater response in the asthmatic group than in the normal group of the accompanying change in the FEV1. The decrements in the FEV1 were not significantly different between the 2 groups after inhaling histamine. This study demonstrates that LTE4 is a potent bronchoconstrictor agonist in humans and suggests that airway responsiveness to this agonist differs substantially with the index of bronchoconstriction used for assessment of airway response.

Aerosols↗
PubMed1987

Chronic exposure to sulfur dioxide. Physiologic and histologic evaluation of dogs exposed to 50 or 15 ppm.

Seven adult mongrel dogs were exposed to SO2 gas at 2 different concentrations (15 and 50 ppm) on a daily basis for 5 to 11 months. Mucous hypersecretion and airway obstruction (a sustained increase in pulmonary resistance) developed in 4 dogs exposed to 50 ppm SO2. Histologic examination of the dogs' airways demonstrated epithelial thickening and an increase in size of the mucous glands. No inflammatory cell infiltration of the airways was noted and, in addition, responsiveness to inhaled histamine and methacholine did not change. The increase in lung resistance correlated with increase in mucous gland volume and airway wall thickening, but not with any change in airway responsiveness. Dogs exposed to 15 ppm SO2 showed minimal histologic and physiologic changes compared with control dogs. Previous work with a similar model of chronic bronchitis, using higher level SO2 exposure, has demonstrated an association of airway inflammation with decreased responsiveness to inhaled bronchoconstrictors. In the present study, with a lower exposure level to SO2 (50 versus 200 ppm), we found similar histologic findings associated with airway obstruction, but in the absence of airway inflammation, responsiveness to inhaled bronchoconstrictors was unchanged. This supports the theory that chronic airway inflammation may be associated with decreased responsiveness to inhaled bronchoconstrictors. This contrasts with the hyperresponsiveness induced by acute exposure to irritant gases noted by others.

Airway Resistance↗
PubMed1987

Sulfur-dioxide-induced bronchitis in dogs. Effects on airway responsiveness to inhaled and intravenously administered methacholine.

Chronic bronchitis was induced in 7 dogs of mixed breed by chronic exposure to SO2 gas. Within the first 2 to 4 wk of exposure, the dogs developed cough and mucous hypersecretion, chronic airway obstruction (increased pulmonary resistance), and persistent lung inflammation as demonstrated by an increase in the number of neutrophils recovered in the bronchoalveolar lavage (BAL) fluid. Airway responsiveness to methacholine aerosol decreased 2- to 3-fold within 8 wk of SO2 exposure. In contrast, airway responsiveness to intravenous administration of methacholine did not change. The data suggest that the decreased airway responsiveness observed during persistent pulmonary inflammation in SO2-exposed dogs is not due to an altered state of airway contractile elements but likely reflects expression of an inhibitory influence of the mucoepithelial barrier.

Airway Resistance↗
PubMed1987

Airway effects of monosodium glutamate in subjects with chronic stable asthma.

We studied the effect of oral monosodium glutamate (MSG) on airways function in 12 subjects with a history of chronic stable asthma in a double-blind, randomized, crossover protocol. Subjects ingested either 25 mg/kg of MSG or sodium chloride (equimolar to MSG) following a 6-hour fast. Spirometry [forced expiratory volume in 1 second (FEV1) and forced vital capacity] was performed before administration of the test substances and for a minimum of 4 hours thereafter. At no time during the observation period was the mean change in FEV1 more negative following MGS than following placebo. MSG is unlikely to be a contributing factor in bouts of bronchospasm in subjects with asthma, and routine avoidance of MSG by individuals with asthma need not be advised.

Adult↗
PubMed1987

Differential effects of calcium channel blockers on leukotriene C4- and D4-induced contractions in guinea pig pulmonary parenchymal strips.

Leukotriene (LT)C4 and LTD4-induced contractile effects in guinea pig pulmonary parenchyma were distinguished by their sensitivity to calcium channel blockers. LTC4-induced contractions were inhibited in a noncompetitive manner in the presence of calcium channel blockers, whereas LTD4 contractions were unaffected. In the presence of diltiazem, maximum LTC4-induced (1 X 10(-7) M) contractions were reduced by 24% and the concentration-effect curve was shifted to the right in a nonparallel manner; diltiazem had no significant effect on the LTD4 response. We used this differential sensitivity to calcium channel blockade to permit pharmacological characterization in guinea pig pulmonary parenchyma of the interaction of the competitive LT blocker FPL55712 and the putative LTD4 receptor, LTRd. We showed, using [3H]LTC4, that at least 15% of LTC4 is converted to LTD4 under our experimental conditions. We performed a Schild analysis of the inhibition of LTD4-induced contractions by FPL55712 in the presence of the calcium channel blocker diltiazem (0.67 mM). The Kb derived from this analysis (3.2 X 10(-7) M) agrees closely with the Ki derived for the interaction of FPL55712 and specific LTD4 binding in lung membranes. A Schild analysis of the interaction of FPL55712 and LTC4 in the presence of diltiazem resulted in competitive inhibition with a Kb of 4.7 X 10(-7) M. This apparent competitive inhibition, combined with the similarity of these binding constants, suggests that diltiazem is effective in blocking LTC4-mediated responses and that when these effects are blocked, LTC4 induced contractions are mediated through LTRd. The differential effects of calcium blockade on these two agonists provides evidence for distinct coupling mechanisms for LT receptors in this tissue.

Animals↗