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C D Wegner

Publications and source records attributed to C D Wegner.

At least 37 records · Page 2Linked to original sources
PubMed1993

Intercellular adhesion molecule-1 expression on the alveolar epithelium and its modification by hyperoxia.

The distribution of intercellular adhesion molecule-1 (ICAM-1) on alveolar epithelial cells and the effects of exposure to 100% O2 on ICAM-1 expression in mouse lungs were studied by EM immunocytochemistry and immunoblot analysis. Cryoultrathin sections from mouse lungs exposed to air or 100% O2 for 84 h were labeled with a monoclonal rat anti-mouse ICAM-1 antibody. In the normal lung, abundant ICAM-1 expression was found on the alveolar surface of type I epithelial cells. Furthermore, ICAM-1 is highly concentrated on the surfaces near cell junctions. ICAM-1 was also found on the capillary surface of endothelial cells and alveolar surface of type II cells at densities considerably lower than that found on type I epithelial cells. After exposure to O2, the labeling density of ICAM-1 on the central surface of type I epithelial cells was not changed significantly. However, the gradient of ICAM-1 on the surfaces near cell junctions was nearly abolished. ICAM-1 labeling on the capillary surface of endothelial cells remained low. ICAM-1 was also markedly induced on the alveolar surface of type II epithelial cells after hyperoxic exposure. These results show that ICAM-1 is expressed primarily on type I epithelial cell surfaces near cell junctions. Exposure to hyperoxia causes a dramatic change in the distribution pattern of ICAM-1 on alveolar type I epithelial cells and induces expression of ICAM-1 on alveolar type II epithelial cells. These hyperoxia-induced changes may influence the associated neutrophil invasion/retention in the alveolar air spaces or alveolar walls.

Analysis of Variance↗
PubMed1993

Control of inflammatory processes by adhesion glycoproteins.

Cell surface adhesive glycoproteins are principal regulators of nearly all aspects of immune/inflammatory responses. Using monoclonal antibodies to individual adhesion molecules, the expression and contribution of specific molecules in the pathogenesis of allergen-induced airway hyperresponsiveness in monkeys has been studied. Results confirm the importance of cell adhesion and demonstrate that antagonism of a single adhesion molecule may provide a novel therapeutic approach.

Animals↗
PubMed1993

A prodrug of a 2,6-disubstituted 4-(2-arylethenyl)phenol is a selective and orally active 5-lipoxygenase inhibitor.

BI-L-226, a 2,6-disubstituted 4-(2-arylethenyl)phenol, is a potent and selective 5-lipoxygenase inhibitor which shows excellent inhibition of antigen-induced leukotriene generation in the lung of cynomolgus monkeys by aerosol administration, although little activity has been observed by the p.o. route. The facile synthesis of the succinate ester BI-L-357, however, results in a prodrug which has p.o. activity between 10 to 30 mg/kg in an ex vivo whole blood model of leukotriene B4 generation in both squirrel and cynomolgus monkeys. In addition, the prodrug is effective in inhibiting pulmonary leukotriene C4 production in antigen-challenged cynomolgus monkeys in the same dose range. Plasma levels of the parent compound in the monkey after p.o. administration of 30 mg/kg are 25-fold higher than the IC50 needed for in vitro inhibition of leukotriene B4 in whole blood. Absolute bioavailability of the parent compound was 50%. The prodrug concept therefore extends the potential of this class of compounds to inflammation sites mediated by 5-lipoxygenase not readily treated by topical administration.

Animals↗
PubMed1992

Intercellular adhesion molecule-1 contributes to pulmonary oxygen toxicity in mice: role of leukocytes revised.

In immature or injured lungs, impaired alveolar gas exchange forces the use of elevated levels of inhaled oxygen to maintain life. But, at high concentrations oxygen induces lung injury, edema, and bronchopulmonary dysplasia, probably by stimulating the generation of reactive oxygen radicals and subsequent neutrophil infiltration. In addition to regulating neutrophil diapedesis, intercellular adhesion molecule-1 (ICAM-1) expression is marked on inflamed alveolar epithelium, suggesting a role for ICAM-1 in oxygen-induced, neutrophil-mediated parenchymal damage. To test this, we evaluated the rat anti-mouse ICAM-1 monoclonal antibody YN1/1.7 in 2 protocols of oxygen-induced toxicity in adult, male Balb-c mice: greater than or equal to 95% O2 for 84 hr and greater than or equal to 95% O2 for 60 hr followed by 48 hr at 21% (ambient) O2. YN1/1.7 treatment partially attenuated the neutrophil infiltration, lung damage (lavage lactate dehydrogenase [LDH] activity) and dysfunction (reductions in respiratory system compliance [Crs] and diffusion capacity of the lungs for carbon monoxide [DLCO] in the 84 hr exposure protocol. In the milder 60 hr exposure protocol, YN1/1.7 completely blocked the oxygen-induced lung dysfunction (reductions in Crs and DLco). These results confirm the contribution of leukocytes in the pathogenesis of pulmonary oxygen toxicity and indicate that antagonism of ICAM-1 may provide a therapeutic approach to reducing hyperoxic lung injury and dysfunction.

Animals↗
PubMed1992

Effects of single and multiple inhalations of platelet-activating factor on airway cell composition and responsiveness in monkeys.

Platelet-activating factor (PAF) is a potent pro-inflammatory mediator that may play a role in the pathogenesis of airway hyper-responsiveness and asthma. In man, a single inhalation of PAF induces a small but prolonged increase in airway responsiveness in some individuals. The purpose of this study was to determine the effects of single and multiple inhalations of PAF on airway cell composition and responsiveness in monkeys. Anaesthetized and intubated adult male cynomolgus monkeys were studied. Airway cell composition was measured by bronchoalveolar lavage (BAL). Airway responsiveness was measured by determining the concentration (PC100) of inhaled methacholine that caused a 100% increase in respiratory system resistance (Rrs). Airway cell composition (BAL) and responsiveness (PC100) were determined 1 day before and 20 hr after a single inhalation of PAF (approximately 200 micrograms) or 3 days before (Day 0) and 3 days after (Day 10) 3-alternate-day (Days 3, 5 and 7) inhalations of PAF (each approximately 600 micrograms). The single inhalation of PAF (n = 8) caused an acute increase in Rrs (147 +/- 69%), an increase in BAL granulocytes, and a decrease in PC100 in four of eight animals that was moderate (greater than eight fold) in only one animal. The mean +/- s.e. change in log PC100 was -0.29 +/- 0.18. The multiple inhalations of PAF (n = 8) caused acute increases in Rrs (143 +/- 38%, 175 +/- 44% and 156 +/- 39%, respectively), an increase in BAL granulocytes, and a decrease in PC100 in four of eight animals that was moderate in two animals. The mean +/- s.e. change in log PC100 was -0.43 +/- 0.22.

Administration, Inhalation↗
PubMed1992

The role of intercellular adhesion molecule-1 in chronic airway inflammation.

We have examined the role of intercellular adhesion molecule-1 (ICAM-1) in chronic airway inflammation and airway hyperresponsiveness in a primate model of asthma. Airway cellular composition was assessed by bronchoalveolar lavage (BAL) and airway responsiveness was measured as the bronchoconstrictor response to inhaled methacholine. In animals with chronic airway inflammation (increased BAL eosinophils) and sustained airway hyperresponsiveness, a 7 day dosing scheme with a murine anti-human ICAM-1 monoclonal antibody (R6.5, 2 mg/kg/day; i.v.) did not reduce the existing airway inflammation or airway hyperresponsiveness. In contrast, a similar dosing scheme with dexamethasone (0.2 mg/kg/day, i.m.) was found to significantly reduce both the airway eosinophilia and hyperresponsiveness. However, one week after cessation of dexamethasone treatment, the airway inflammation and hyperresponsiveness returned to pre-treatment levels. In further experiments where animals were first treated with dexamethasone (7 days) followed by a 7 day treatment with R6.5, the reoccurrence of airway inflammation and subsequent increase in airway responsiveness was prevented. We conclude that the efficacy of ICAM-1 is primarily associated with inhibition of the influx of inflammatory cells into the airways and subsequent reduction in airway responsiveness. These data suggest that in lungs with pre-existing inflammation the modulation of ICAM-1 following treatment with glucocorticoids may be a novel and more selective long-term treatment for control of the chronic airway inflammation and hyperresponsiveness associated with bronchial asthma.

Airway Resistance↗
PubMed1992

The onset and recovery from airway hyperresponsiveness: relationship with inflammatory cell infiltrates and release of cytotoxic granule proteins.

Previous studies from our laboratory have demonstrated a temporal relationship between eosinophil influx into the airways and the onset of airway hyperresponsiveness to inhaled methacholine. The purpose of the present study was to extend this observation by evaluating changes in airway cellular composition and measuring the levels of granulocyte-derived mediators recovered in BAL fluid during the onset and recovery from antigen-induced airway hyperresponsiveness. Airway cellular composition, airway responsiveness to inhaled methacholine and the levels of BAL fluid EPO and MPO were monitored over a 32 day study in eight adult male Ascaris suum sensitive cynomolgus monkeys. Repeated Ascaris suum inhalation (nine challenges during days 0-21) resulted in a selective, sustained airway eosinophilia that was temporally related with the onset and maintenance of airway hyperresponsiveness (r = 0.67, P less than 0.001). The level of BAL eosinophil-derived EPO was increased and remained elevated concurrent with the increase in airway eosinophils and airway responsiveness. During the recovery phase (days 22-32) the actual number of eosinophils remained elevated, while BAL EPO levels were significantly decreased. The recovery phase was also associated with a transient increase in the number of BAL neutrophils and MPO concentration. We conclude that the number and state of activation of airway eosinophils directly correlate with the onset and maintenance of airway hyperresponsiveness. Recovery from airway hyperresponsiveness is associated with a decrease in eosinophil activation and a transient increase in the number of activated neutrophils.

Airway Resistance↗
PubMed1992

Antigen-induced acute and late-phase responses in primates.

We have examined the proinflammatory cell influx as well as the levels of eosinophil and neutrophil-derived granule proteins in BAL fluid obtained from monkeys undergoing acute and late-phase (dual) or single acute bronchoconstriction following antigen inhalation. Prior to antigen inhalation, there was a significantly higher number (and percentage) of eosinophils in BAL fluid from dual responder monkeys as compared with single responders. The late-phase response (LPR) (6 to 8 h postantigen) was associated with a decrease in the number of BAL eosinophils and an increase in the levels of BAL fluid EPO that returned to baseline levels by 24 h postantigen inhalation. In contrast, the number of BAL neutrophils prior to antigen inhalation were low. Concurrent with the LPR, the number of BAL neutrophils and the concentration of EPO in BAL fluid were significantly increased above that occurring in single responders. Chronic treatment (7 days) with dexamethasone significantly reduced the number of BAL eosinophils and the BAL levels of EPO prior to antigen inhalation in dual responder (LPR) monkeys and significantly blocked the dual response and both the associated neutrophil influx into the airways and an increase in BAL fluid EPO during the LPR. We conclude that, in this primate model, eosinophil activation and a large influx of neutrophils into the airways is associated with the occurrence of the antigen-induced late-phase airway obstructive response.

Acute-Phase Reaction↗
PubMed1992

Polymyxin B-induced bronchial neutrophilia does not alter airway responsiveness to methacholine in cynomolgus monkeys.

The purpose of this study was to develop a primate model of chronic bronchial neutrophilia to investigate the role of neutrophils in the pathogenesis of airway hyperresponsiveness. Ten adult male cynomolgus monkeys (Macaca fascicularis) were anaesthetized and intubated for each study. Six animals each received a total of seven inhalation treatments with polymyxin B (200 micrograms) over a 24 day period. Four control animals received an identical treatment regime with vehicle inhalations. Airway cellular composition was assessed by bronchoalveolar lavage (BAL). Airway responsiveness was assessed by methacholine cumulative dose response determinations. There were no significant changes in airway cellular composition or airway responsiveness in the control group. In contrast, Polymyxin B inhalation resulted in an influx of neutrophils (PMN) into the lungs which peaked at day 10 of the study (%PMN in BAL fluid rose from 5 +/- 2 to 51 +/- 8, P less than 0.001) and persisted out to day 24 (41 +/- 8, P less than 0.01). Increases in PMNs were associated with an increase in BAL levels of myeloperoxidase (MPO levels in BAL fluid increased from 2 +/- 3 to 180 +/- 23 OD P less than 0.05). Although airway PMN percentages and MPO concentrations were chronically elevated, airway responsiveness did not change. These results suggest that the neutrophil does not play a functional role in the onset of hyperresponsive airways in primates.

Administration, Inhalation↗
PubMed1991

BI-L-239, a 5-lipoxygenase inhibitor, blocks inhaled antigen-induced airway hyperresponsiveness in conscious guinea pigs.

Male Hartley guinea pigs were actively sensitized to ovalbumin (OA). Respiratory system resistance (Rrs) was measured by forced oscillations superimposed on tidal breathing. Airway responsiveness (inhaled methacholine PC100) was determined three days prior and three days after (day 10) three alternate day inhalations of OA. Airway cell composition was assessed on day 10 by lung lavage. Three groups (n = 5-6) were studied: A) vehicle challenged, B) OA challenged/placebo treated, C) OA challenged/BI-L-239 (2,6-dimethyl-4-[2-(4-fluorophenyl)ethenyl]phenol) treated (10 x 0.75 mg/actuation, 10 minutes prior to each OA challenge). Animals were treated with pyrilamine and indomethacin (10 mg/kg i.p.) 30 minutes prior to each OA challenge. OA induced acute increases in Rrs of 143 +/- 29%, 238 +/- 73% and 102 +/- 43% in placebo and 86 +/- 34%, 45 +/- 35% (p, 0.05 vs. placebo) and 102 +/- 31% in BI-L-239 treated. OA induced a significant (p less than 0.05) increase in airway leukocytes in placebo (487 +/- 36 to 1615 +/- 421 x 10(3)/ml) but not BI-L-239 treated (to 881 +/- 155 x 10(3)/ml) and decrease in methacholine PC100 in placebo (1.487 +/- 0.49 to 0.39 +/- 0.18 mg/ml) but not BI-L-239 treated (0.99 +/- 34 to 1.04 +/- 0.39 mg/ml). We conclude that BI-L-239 attenuates the airway constriction, inflammation and hyperresponsiveness induced by repeated antigen inhalations in conscious guinea pigs.

Administration, Inhalation↗
PubMed1991

Effects of single and multiple inhalations of antigen on airway responsiveness in monkeys.

Airway hyperresponsiveness is an important and characteristic feature of asthma. In monkeys, we have reported that antigen (Ag) inhalation induces a prolonged airway eosinophilia, that chronic airway eosinophilia is associated with marked airway hyperresponsiveness, and that chronic Ag inhalations induce airway eosinophilia and hyperresponsiveness. In this study we have determined the effects of acute Ag inhalation(s) on airway responsiveness to obtain a protocol for the study of the mechanisms involved. Anesthetized and intubated adult male cynomolgus monkeys with a naturally occurring sensitivity to Ascaris suum extract were studied. Airway responsiveness (provocative concentration of nebulized and inhaled methacholine that induced a 100% increase in respiratory system resistance [Rrs] [PC100]; twofold decrease regarded as significant) and airway cell composition (bronchoalveolar lavage [BAL]) were determined 1 day before and 20 hours after a single inhalation of Ascaris extract, or 3 days before and 3 days after three alternate-day inhalations of Ascaris extract. The single inhalation of Ag (N = 7) caused an acute increase in Rrs (307% +/- 62%), an increase in BAL leukocytes, and a decrease in PC100 in three animals that was moderate (more than eightfold) in two animals. The mean +/- SE change in log PC100 was only -0.25 +/- 0.24. The multiple inhalations of Ag in the same animals caused acute increases in Rrs (178% +/- 48%, 380% +/- 83%, and 331% +/- 63%, respectively), an increase in BAL granulocytes, and a decrease in PC100 in six of seven animals (mean +/- SE change in log PC100 was -1.36 +/- 0.34) that was moderate in two and severe (more than 80-fold) in three animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1991

Inflammation and cell-cell interactions in airway hyperresponsiveness.

Airway hyperresponsiveness results from the conversion of normally reactive airways to a state of augmented responsiveness to constrictor stimuli. Although the mechanism accounting for the induction of airway hyperresponsiveness remains elusive, recent investigations have suggested that inflammation may be a sine qua non for human asthma. Numerous experimental models have demonstrated the necessity of circulating granulocytes as mediators of augmented bronchoconstriction during immune challenge. It is not known how granulocytes are targeted for selective migration to the conducting airways of the lung during hyperresponsive states; however, recent evidence implicates the upregulation of granulocyte adhesion molecules on both the endothelial and epithelial surfaces of the airway. There is evidence that during migration diapedesis, granulocytes interact with epithelial and endothelial cells to produce regionally secreted mediators that upregulate the responsiveness of adjacent airway smooth muscle and/or cause lumenal edema, thus augmenting the effect of constrictor stimuli. Most evidence suggests that the eosinophil is the most important granulocyte in these responses and that eosinophilic infiltration and activation may account for the unique, spasmodic, and cyclic nature of hyperreactive airways. The molecular biology of the eosinophil granule proteins has characterized four distinct substances, each of which exerts potential cytotoxic effects on airway epithelium by different mechanism. In addition, at least one of these proteins, the major basic protein, appears to cause direct, noncytotoxic stimulation of epithelial secretion that upregulates nonspecifically the response of airway smooth muscle to contractile stimuli. The recognition of inflammation as the essential component to airway hyperresponsiveness provides a fresh approach to a difficult problem and suggests a host of novel therapies for human asthma.

Amino Acid Sequence↗
PubMed1991

Antigen-induced mediator release in primates.

We examined the release of bronchoactive mediators into the airways of allergic primates during the acute response to specific antigen inhalation. Twelve adult male cynomolgus monkeys (Macaca fascicularis) with a naturally occurring respiratory sensitivity to inhaled Ascaris suum extract were anesthetized and intubated for each study. Respiratory system resistance (Rrs) and dynamic lung compliance (CLdyn) were measured before and after antigen inhalation, and the release of mediators into the airways was assessed by bronchoalveolar lavage (BAL). BAL samples were concentrated approximately 5-fold before quantitation of LTC4 and PGD2 by RP-HPLC and radioimmunoassay and histamine by a fluorometric assay. Antigen inhalation resulted in a 40-fold increase in BAL levels of i-LTC4 (1.5 +/- 0.7 to 41.6 +/- 12.7 ng, p less than 0.01), a 10-fold increase in i-PGD2 (2.4 +/- 0.9 to 25.9 +/- 5.5 ng, p less than 0.01), and a 20-fold increase in BAL histamine (1.0 +/- 1.5 to 21.4 +/- 2.3 micrograms, p less than 0.01). Dexamethasone (n = 7) inhibited the antigen-induced increase in BAL i-LTC4 (71 +/- 6%, p less than 0.01) and i-PGD2 (52 +/- 8%, p less than 0.05) while weakly inhibiting histamine release (43 +/- 10%). Indomethacin (n = 7) had a variable effect on i-LTC4 levels (6 +/- 51%), strongly inhibited i-PGD2 (88 +/- 9%, p less than 0.01), and had no effect on histamine release (25 +/- 8%). Pretreatment with iodoxamide tromethamine significantly blocked the release of each mediator, but mepyramine, an H1 antagonist, had no effect on mediator release.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1991

Endothelial leukocyte adhesion molecule-1 mediates antigen-induced acute airway inflammation and late-phase airway obstruction in monkeys.

This study examines the role of endothelial leukocyte adhesion molecule-1 (ELAM-1) in the development of the acute airway inflammation (cell influx) and late-phase airway obstruction in a primate model of extrinsic asthma. In animals sensitive to antigen, a single inhalation exposure induced the rapid expression of ELAM-1 (6 h) exclusively on vascular endothelium that correlated with the influx of neutrophils into the lungs and the onset of late-phase airway obstruction. In contrast, basal levels of ICAM-1 was constitutively expressed on vascular endothelium and airway epithelium before antigen challenge. After the single antigen exposure, changes in ICAM-1 expression did not correlate with neutrophil influx or the change in airway caliber. This was confirmed by showing that pretreatment with a monoclonal antibody to ICAM-1 did not inhibit the acute influx of neutrophils associated with late-phase airway obstruction, whereas a monoclonal antibody to ELAM-1 blocked both the influx of neutrophils and the late-phase airway obstruction. This study demonstrates a functional role for ELAM-1 in the development of acute airway inflammation in vivo. We conclude that, in primates, the late-phase response is the result of an ELAM-1 dependent influx of neutrophils. Therefore, the regulation of ELAM-1 expression may provide a novel approach to controlling the acute inflammatory response, and thereby, affecting airway function associated with inflammatory disorders, including asthma.

Acute Disease↗
PubMed1991

Adhesion molecules in the pathogenesis of asthma.

Using a primate antigen inhalation model the mechanisms involved in the induction of airway hyperresponsiveness were studied. Antigen inhalation induced a prolonged airway eosinophilia. Chronic airway eosinophilia, intratracheal instillation of eosinophil major basic protein, repeated antigen inhalation, and airway epithelial desquamation induced, or were associated with, an increase in airway responsiveness. Using monoclonal antibodies to intercellular adhesion molecule-1 (ICAM-1) and endothelial-leukocyte adhesion molecule-1 (ELAM-1), the contributions of these cell adhesion molecules to antigen-induced airway hyperresponsiveness were studied. ICAM-1 partially mediated eosinophil adhesion to endothelium in vitro, was upregulated on inflamed endothelium and epithelium in vitro and in vivo, and contributed to repeated antigen-induced airway eosinophilia and hyperresponsiveness. ELAM-1 was upregulated on inflamed endothelium (but not epithelium) in vitro and in vivo, but did not contribute to the repeated antigen-induced airway eosinophilia and hyperresponsiveness. These results indicate that antagonism of ICAM-1, but not ELAM-1, may provide a novel therapeutic approach to reducing the airway inflammation and hyperresponsiveness commonly found in asthmatics.

Administration, Inhalation↗