Biomedical subjects

C D Wegner

Publications and source records attributed to C D Wegner.

44 records · Page 3Linked to original sources

PubMed1991

The effects of a 5-lipoxygenase inhibitor on antigen-induced mediator release, late-phase bronchoconstriction and cellular infiltrates in primates.

Inhaled BI-L-239 significantly inhibited i-LTC4 generation, late-phase bronchoconstriction and the influx of neutrophils into the lungs. We conclude that leukotriene generation and release within the lungs, following allergen exposure, in part mediate altered lung function and contribute to the development of airway inflammation. As such, treatment with a selective 5-lipoxygenase inhibitor may aid in the treatment of bronchial asthma and other allergic diseases.

Administration, Intranasal↗

PubMed1990

Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma.

Airway eosinophilia, epithelial desquamation, and hyperresponsiveness are characteristics of the airway inflammation underlying bronchial asthma. The contribution of intercellular adhesion molecule-1 (ICAM-1) to eosinophil migration and airway responsiveness was studied. ICAM-1 partially mediated eosinophil adhesion to to endothelium in vitro and was upregulated on inflamed bronchial endothelium in vivo. ICAM-1 expression was also upregulated on inflamed airway epithelium in vitro and in vivo. In a primate model of asthma, a monoclonal antibody to ICAM-1 attenuated airway eosinophilia and hyperresponsiveness. Thus, antagonism of ICAM-1 may provide a therapeutic approach to reducing airway inflammation, hyperresponsiveness, and asthma symptoms.

Animals↗

PubMed1990

Effect of structure on potency and selectivity in 2,6-disubstituted 4-(2-arylethenyl)phenol lipoxygenase inhibitors.

A series of 2,6-disubstituted 4-(2-arylethenyl)phenols with potent human neutrophil 5-lipoxygenase (5-LO) inhibiting activity (IC50S in the 10(-7) M range) and weaker human platelet cyclooxygenase (CO) inhibiting activity (IC50S in the 10(-6) M range) is described. This series evolved from the chemical modification of an antiinflammatory dual CO/5-LO inhibitor, 2,6-di-tert-butyl-4-[2-(3-pyridyl)ethenyl]phenol (BI-L-93 BS). The potency and selectivity for 5-LO inhibition is greatly influenced by the nature of the substituents in the 2- and 6-positions. Other structure-activity relationships that determine relative 5-LO and CO potency are discussed. In vivo activity against antigen-induced leukotriene-mediated bronchoconstriction and cell influx in guinea pigs is presented. Representatives of the series are active when administered at 30 mg/kg ip.

Animals↗

PubMed1990

Repeated antigen inhalation results in a prolonged airway eosinophilia and airway hyperresponsiveness in primates.

The effects of repeated antigen inhalation on airway cellular composition and airway responsiveness were examined in primates. Airway cellular composition was assessed by bronchoalveolar lavage (BAL), and airway responsiveness was measured as the bronchoconstrictor response to cumulative methacholine dose-response determinations over the course of a 10-wk study. Control animals, exposed to repeated vehicle inhalation challenges, were tested in parallel with the antigen-challenged group. Repeated antigen inhalation resulted in a prolonged inflammatory reaction characterized by a large increase in airway eosinophils (3 +/- 1 to 59 +/- 15%, P less than 0.01). Airway eosinophilia was associated with an increase in airway responsiveness as indicated by a leftward shift in the methacholine dose-response curves, an increase in the slope of the dose-response curves, and a decrease in PC100 values (the dose of methacholine required to cause a 100% increase in lung resistance). The number of BAL eosinophils and the level of eosinophil major basic protein in BAL correlated significantly with methacholine PC100 values (r = 0.61, P less than 0.01 and r = 0.64, P less than 0.01, respectively). Histological examination of lung biopsy samples taken at week 10 of the study demonstrated a striking infiltration of eosinophils in the antigen-challenged animals. These results support earlier observations that demonstrated an association between increases in airway eosinophils and increases in airway responsiveness and suggest that eosinophils are involved in the pathogenesis of hyperresponsive airways.

Administration, Inhalation↗

PubMed1989

Antigen-coated sepharose beads induce airway eosinophilia and airway hyperresponsiveness in cynomolgus monkeys.

A method of inducing sustained airway eosinophilia and airway hyperresponsiveness in primates has been developed. Our method utilizes a series of intratracheal instillations of Ascaris suum-coated sepharose 4B beads (3 x 10(5] administered once a week for four weeks. Five cynomolgus monkeys (Macaca fascicularis) demonstrating a naturally occurring skin and respiratory sensitivity to Ascaris suum extract were studied. Airway cell composition was measured by bronchoalveolar lavage (BAL), and airway responsiveness was determined as the bronchoconstrictor response to inhaled methacholine. Ascaris suum bead administration resulted in a transient increase in total cells recovered by BAL (2.4 +/- 0.4 to 8.7 +/- 2.5 x 10(5) cells/ml, p less than 0.05) and a selective increase in BAL eosinophils (17 +/- 6 to 916 +/- 158 x 10(3) cells/ml, p less than 0.05). Increases in airway responsiveness were concurrent with the increase in airway eosinophils. These observations show that airway eosinophilia is associated with airway hyperresponsiveness in primates. Furthermore, this new model is a novel experimental system in which the underlying mechanisms in the pathogenesis of airway hyperresponsiveness can be investigated.

Airway Resistance↗

PubMed1988

Acute pulmonary response to cotton bract extract in monkeys: lung function and effects of mediator modifying compounds.

It is well established that cotton dust inhalation can compromise lung function in textile workers. Challenges with a water-soluble extract of cotton bract (CBE) can also induce reversible airway obstruction in healthy volunteers. We have examined the effect of inhaled CBE in nonhuman primates and have attempted to inhibit the bronchoconstrictive response with mediator modifying compounds. CBE (34 mg/ml or 100 mg/ml) was administered via IPPB for 15 minutes (15 breaths/min) in 12 intubated, anesthetized, adult male monkeys (Macaca fascicularis). Breath-by-breath determinations of pulmonary resistance, dynamic compliance (Cdyn), tidal volume, and breathing frequency were calculated from the transpulmonary pressure (esophageal balloon) and airflow signals and monitored for 2 hr postchallenge. Control challenges with distilled water were also performed in 3 monkeys with the greatest response from CBE. Five animals (42%) were found to respond to CBE with peak % changes in Cdyn greater than 45%. In 3 of these animals, we attempted to blunt the CBE response with chlorpheniramine (0.1 mg/kg i.v.) and a mast cell stabilizer lodoxamide (0.1 mg/ml aerosol). In these 3 animals the mean (+/- SD) peak % changes in Cdyn to CBE alone was -47.4 +/- 1.8. The CBE response following chlorpheneramine was -49 +/- 15.7 and following lodoxamide was -47.0 +/- 5.4. These data suggest that monkeys, like humans, can develop reproducible bronchoconstriction following an aerosol challenge with CBE. Furthermore, this bronchoconstriction in the monkey is probably not explained by the action of histamine or mediator release alone and an acute inflammatory reaction may be involved.

Animals↗

PubMed1986

Linear-lumped-parameter modeling of pulmonary impedance in monkeys.

Pulmonary impedance, ZL, measured from 2 to 32 Hz in anesthetized, intubated and paralyzed bonnet monkeys (Macaca radiata) was fitted to a variety of linear-lumped parameter mechanical networks. Parameter values for each network were obtained by minimizing the average of the percent distance, Dr, between the computed network impedance and measured ZL at all frequencies. Measured resistance, RL, decreased from 2 to 8 Hz and increased from 8 to 32 Hz indicating that a single series resistance-inertance-compliance (RIC) network was not optimal (Dr approximately 19%). Networks consisting of two series RIC pathways in parallel resulted in a lower Dr (approximately 14%), but parameter values were difficult to interpret. Despite not modeling the decrease in RL with frequency below 8 Hz, an airway wall compliance, Caw, network in which the airways were separated into central and peripheral components resulted in an even lower Dr (approximately 11%). In addition, parameter values were easy to interpret, consistent among our "normal" monkeys and changed consistently and explainably with change in lung mechanics induced by decrease in lung volume. We conclude that networks containing both parallel pathways and Caw are necessary to model ZL over the entire frequency range (2-32 Hz), the effect of Caw is an important determinant of ZL above 8 Hz, and a six-parameter Caw network with the ratio of Caw to parenchymal compliance, Cp, fixed may prove useful in interpreting changes in ZL induced by alterations in lung mechanics in monkeys.

Airway Resistance↗

PubMed1984

Dynamic respiratory mechanics in monkeys measured by forced oscillations.

We measured impedances of the lungs (ZL) and respiratory system (Zrs) by discrete frequency (f) forced oscillations in adult bonnet monkeys at two lung volumes, FRC and at transrespiratory system pressure (Prs) of -5 cm H2O. Measurements were made from 2 to 32 Hz to study f dependence of effective resistances (Reff) and reactances, and from 1 to 8 Hz to study f dependence of effective pulmonary compliance (Ceff,L). Estimates of resistances (R), inertances (I) and compliances (C) of the lungs (L), chest wall (W) and respiratory system (rs) were obtained by fitting the 2-32 Hz data to a series RIC network model. Reff,L, Reff,W and Reff,rs were found to be f dependent. The magnitude of ZL was small relative to that of Zrs at all f with RL only 30% of Rrs and CL six times Crs. Decreasing lung volume from FRC to Prs = -5 cm H2O increased RL, RW and Rrs, slightly decreased CL, CW and Crs, slightly increased resonance frequencies, and increased the f dependent behavior of Ceff,L. Our results indicate both similarities and differences between the respiratory system of these primates and man.

Airway Resistance↗