Biomedical subjects
S E Wenzel
Publications and source records attributed to S E Wenzel.
Single oral dose of prednisone decreases leukotriene B4 production by alveolar macrophages from patients with nocturnal asthma but not control subjects: relationship to changes in cellular influx and FEV1.
BACKGROUND: Nocturnal worsening of asthma is associated with an increase in numbers of airway inflammatory cells during the early morning. However, cell function during the night, with and without administration of steroids, has not been investigated. OBJECTIVE: This study was designed to determine the effect of prednisone on pulmonary alveolar macrophage production of leukotriene B2 and thromboxane B2 at night and how it relates to changes in pulmonary function and cellular influx. METHODS: Alveolar macrophages were obtained from patients with nocturnal asthma, patients with nonnocturnal asthma, and normal control subjects at 4:00 AM by bronchoalveolar lavage after administration of placebo and prednisone. Cells were placed in limited cell culture, and eicosanoids were measured from baseline and stimulated cells. RESULTS: Patients with nocturnal asthma had both a significantly greater fall in forced expiratory volume in 1 second (FEV1) and a greater influx of neutrophils and eosinophils at 4:00 AM than normal subjects after placebo treatment, whereas patients with nonnocturnal asthma had intermediary responses. There was no difference in baseline or stimulated LTB4 production during placebo administration in the three groups. After prednisone treatment, there was an improvement in the nocturnal fall in FEV1 and a significant decrease in the neutrophil influx in patients with nocturnal asthma compared with the other groups. These changes were accompanied by a significant decrease in the stimulated LTB4 production in patients with nocturnal asthma compared with a small increase in both patients with nonnocturnal asthma and normal subjects. Thromboxane B2 production did not change. The decrease in LTB4 production was correlated with the fall in granulocytic cells and improvement in the nocturnal FEV1. However, the two variables with the greatest combined influence on the improvement in FEV1 were the decrease in stimulated LTB4 production and the fall in neutrophil influx. CONCLUSIONS: We demonstrate for the first time that a single oral dose of prednisone decreases LTB4 production from alveolar macrophages, obtained at night from patients with nocturnal asthma, during a time of known inflammation. Further, this decrease in stimulated production is associated with decreases in cellular influx and improvement in pulmonary function.
Blood and bronchoalveolar lavage endothelin-1 levels in nocturnal asthma.
Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that was recently shown to exhibit bronchoconstrictive properties in vitro. In asthmatic patients, the expression of ET-1 peptide was also shown to be increased in endobronchial biopsies. Thus, we postulated that ET-1 could be higher in subjects with nocturnal asthma. Bronchoalveolar lavage (BAL) fluid levels of ET-1 were measured in 10 subjects with nocturnal asthma and 6 normal volunteers at 0400 h (nighttime groups) and in an additional 7 subjects with nocturnal asthma and 6 control subjects at 1600 h (daytime groups). ET-1 levels were significantly lower in the nighttime asthmatic group (median 39.3 pg/mg protein, 7.3 to 44.0 IQ) than in the nighttime control group (median 77.4 pg/mg protein, 46.8 to 121.9 IQ; p = 0.01) or the daytime asthmatic group (median 56.8 pg/mg protein, 51.6 to 97.4 IQ; p = 0.04). ET-1 levels did not differ significantly between the daytime asthmatic and the daytime control groups or between control groups. Additionally, the overnight reduction in lung function was significantly correlated with lower BAL ET-1 levels (r = 0.57, p = 0.05). These results suggest that ET-1 plays a role in the overnight worsening of asthma and perhaps is more tightly tissue bound, resulting in lower levels of BAL fluid.
Asthma as an inflammatory disease.
Asthma has been described primarily as an inflammatory process only in the last 5 to 10 years. Previously, it was thought of primarily as a disease of nerves and smooth muscle. This inflammatory process is now considered to be an immunologically initiated, mediator-driven event. The observation that asthma is associated with an inflammatory process in the lungs has dramatically changed our understanding of the pathophysiology and treatment of this disease. Like many other theories that have undergone a significant change in direction, it is possible that over the next few years the pendulum will begin to swing back. The nerves and smooth muscles may (or may not) be implicated directly again. It is conceivable that in addition to an inflammatory process, underlying alterations in the architecture of the lungs will also be found. These alterations might serve to amplify the effects of inflammation, thereby leading to the clinical manifestations of asthma.
Peritoneal lavage fluid alters patterns of eicosanoid production in murine bone marrow-derived and peritoneal macrophages: dependency on inflammatory state of the peritoneum.
Murine resident macrophages produce an abundance of eicosanoids, whereas elicited macrophages produce lesser quantities of eicosanoids in general, and leukotriene C4 (LTC4) and prostacyclin (PGI2) in particular. Macrophage precursors derived from bone marrow cells produce even smaller amounts. We postulated that these differences may be regulated by substances found in the microenvironment of the cell, which may alter arachidonate release from phospholipid and its subsequent metabolism to eicosanoids. To examine if inherent differences in phospholipid availability contributed to the observed differences in eicosanoid synthesis among these three groups of macrophages, we monitored uptake and release of arachidonic acid (AA) in resident and elicited peritoneal macrophages and in bone marrow-derived macrophages (BMDM). Although differences existed in the extent of arachidonate release (37% vs. 22% vs. 27% release), the differences were not enough to explain the much larger differences in eicosanoid production. We therefore determined whether the AA cascade enzymes, including phospholipase A2 (PLA2) were intact by adding exogenous AA to the three cell types. PGI2 synthesis was not significantly increased in either elicited or BMDM. However, the enzymes necessary for LTC4 production appeared intact in elicited cells but not in BMDM. To further characterize the differences in eicosanoid synthesis between resident and elicited peritoneal macrophages and BMDM, we determined if a variety of exogenous substances [growth factors, cytokines, and noninflammatory and inflammatory peritoneal lavage fluid (NPLF and IPLF)] could enhance the production of LTC4 and PGI2 in those macrophage groups. The addition of granulocyte-macrophage colony stimulating factor (GM-CSF) slightly increased LTC4 production by BMDM and elicited macrophages. In contrast, NPLF increased the production of both LTC4 and PGI2 from BMDM, while IPLF had no effect. A similar effect of NPLF was seen on LTC4 (but not PGI2) production from elicited peritoneal cells, while IPLF decreased both LTC4 and PGI2 production from resident peritoneal macrophages. These studies indicate that substances found in the peritoneum of mice can enhance or diminish the production of LTC4 and PGI2 from the macrophage. This regulation appears to depend on the inflammatory state of the peritoneum.
Inactivation of leukotriene C4 in the airways and subsequent urinary leukotriene E4 excretion in normal and asthmatic subjects.
Leukotrienes (LT) are synthesized in the lung during asthmatic reactions and mediate certain inflammatory symptoms. Pulmonary metabolism and clearance of exogenously added peptidoleukotrienes were studied in nonasthmatics, asthmatics, and asthmatics challenged with allergen. [3H]LTC4 and [14C]dextran were instilled into the airways, and bronchoalveolar lavage fluid (BALF) was obtained 15 min later. After comparing the [3H]/[14C] ratio of the instilled solution with that in BALF, 77% of LT were found to have been removed from the airways of nonasthmatics, and 72% of unchallenged asthmatics. Allergen administration to asthmatics 1 min before LT instillation inhibited LT transfer out of the airways by 26%, compared with asthmatics not challenged with allergen. This decrease in the removal of LT from the airways during allergic reactions could potentiate the physiologic effects of LT produced in the airways. The predominant LT in BALF was LTE4, constituting 56% of the LT in asthmatics and 61% in nonasthmatics. The percentage of LTE4 in BALF increased to 87% in allergen-stimulated asthmatics (p < 0.05 compared with the two other groups), this again reflecting decreased transfer of LT out of the lung rather than an increase in metabolism. Urinary excretion of LT metabolites occurred rapidly, the majority being excreted excreted within 6 h after instillation. LTE4, the major urinary LT metabolite identified by high-performance liquid chromatography, was a similar percentage concentration in the three groups and, thus, can be accurately used as an index of LT synthesis.
Inflammatory cells and eicosanoid mediators in subjects with late asthmatic responses and increases in airway responsiveness.
To determine the relationship of inflammatory cells and eicosanoid mediators to the pathogenesis of the late asthmatic response (LAR) and increases in nonspecific airway responsiveness, we studied bronchoalveolar lavage (BAL) cells and fluid in 27 subjects 12 hours after inhaled antigen challenge. Methacholine challenge was performed before antigen challenge and 24 hours later (12 hours after BAL). Eight subjects had no LAR (-LAR, less than or equal to 10% fall in FEV1), nine subjects had an equivocal LAR (+/- LAR, 11% 25% fall in FEV1), and 10 subjects had a definite LAR (+LAR, greater than 25% fall in FEV1). Subjects developing +LAR had increased airway responsiveness at baseline compared with that of subjects developing an +/- LAR, but not with subjects having -LAR. If airway responsiveness was markedly increased at baseline, further increases after antigen challenge were often not observed. We found that both percent neutrophils and eosinophils increased in BAL as the severity of the LAR increased, but significant differences between the groups with -LAR and +LAR were only observed when both cell types were considered together. In addition, there was a significant correlation between the combined cell percentages and the severity of the LAR as determined by fall in FEV1. Likewise, increases in airway responsiveness were associated with significant increases in both neutrophil and eosinophil numbers, but only neutrophils correlated with the change in airway responsiveness after antigen challenge. However, despite the significant physiologic and cellular differences that we found between our groups, no significant differences could be found in BAL eicosanoid-mediator concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Bronchoalveolar lavage fluid mediator levels 5 minutes after allergen challenge in atopic subjects with asthma: relationship to the development of late asthmatic responses.
Inflammatory mediators have been implicated in the pathogenesis of human asthma and have been demonstrated to increase in bronchoalveolar lavage fluid during the time of the immediate asthmatic response (IAR) after allergen instillation in the lungs. However, the relationship of these mediators, measured early to the late asthmatic response (LAR), airway reactivity, and clinical asthma, is unknown. In the present study, we evaluated mediator levels in bronchoalveolar lavage fluid before and 5 minutes after allergen challenge from three subject groups: atopic subjects without asthma (N = 7), atopic subjects with asthma and without LAR [-) LAR) (N = 6), and atopic subjects with asthma and with LAR [+) LAR) (N = 6). Subjects with asthma were differentiated into subjects with and without LARs based on at least a 15% decrease in FEV1 between 3 to 8 hours postallergen inhalation. The mediators, prostaglandin D2 thromboxane B2 leukotriene C4 (LTC4), and histamine, were measured both before and after allergen instillation. Baseline prechallenge levels were similar, except in the case of LTC4. LTC4 was detectable at baseline significantly more frequently in the atopic subjects with asthma with and without LAR when these subjects were compared to the atopic subjects without asthma (nine of 12 detectable versus one of seven detectable). In all groups, significant increases in mediator levels were observed in the groups with asthma postallergen challenge, compared to the atopic subjects without asthma. Atopic subjects with asthma and without LAR had significantly higher levels of all four mediators after challenge than atopic subjects with asthma and with LAR and atopic subjects without asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
Urinary leukotriene E4 in patients with asthma. Effect of airways reactivity and sodium cromoglycate.
A group of 17 patients with allergic asthma was challenged with aerosolized antigen, and the excretion of the peptidoleukotriene metabolite leukotriene (LT) E4 in the urine was determined as an index of leukotriene synthesis. The allergen challenge caused a drop in FEV1 of 25 to 59% within the first 2 h in all patients. This was associated with an increase in urine LTE4 excretion during the subsequent 12 h. The amount of urinary LTE4 excreted increased from a 12-h baseline level of 46 +/- 6.8 ng to a postallergen challenge level of 92 +/- 13 ng. In a similar experimental protocol methacholine challenge alone did not significantly increase urinary LTE4 excretion. In comparing all individuals as a group, there was no significant positive correlation between the magnitude of the drop in FEV1 during the immediate asthmatic response (IAR) and the increased amount of LTE4 excreted in the urine (p = 0.08). These parameters were still not significantly correlated when airways reactivity (log PC20) was also considered (p = 0.057). However, when each individual was compared to self in the presence and absence of cromoglycate, a significant correlation was found to exist between the drop in FEV1 during the IAR, the excretion of urinary LTE4, and the airways reactivity. No correlation was found between the increase in urine LTE4 excreted during the 12 h following allergen challenge and the severity of late (3 to 12 h) responses to allergen, but there was a significant prolonged (12 to 36 h) elevated urine LTE4 excretion in those patients with the most severe late asthmatic response.(ABSTRACT TRUNCATED AT 250 WORDS)
Measurement of peptidoleukotrienes in biological fluids.
Samples of human bronchoalveolar lavage fluid (BALF) and urine were utilized to demonstrate methods for quantitation and validation of leukotrienes (LTs). These methods utilize an enzyme immunoassay (EIA) that uses commercially available reagents, the antibody recognizing LTC4, LTD4, LTE4, and N-acetyl LTE4. BALF containing epithelial lining fluid was collected from atopic asthmatics both before and 5 min after the subjects had been challenged with a local instillation of allergen into the airways. BALF samples collected without allergen challenge had low levels of immunoreactive LTs, whereas samples collected after allergen were markedly elevated. After high-performance liquid chromatography (HPLC) separation of LTs, EIA revealed the presence of LTC4. The identity was validated by incubating LTC4 with a bovine gamma-glutamyl transpeptidase with dipeptidase activity that converted added [3H]-LTC4 as well as LTC4 immunoreactivity to LTE4. Urine samples collected from six healthy volunteers, one patient with adult respiratory distress syndrome (ARDS), and three patients in status asthmaticus were also analyzed for LTs. After HPLC separation of LTs and quantitation by EIA, urine samples from healthy subjects were found to have low but measurable LTE4. In contrast, the urine samples from the patients in status asthmaticus and from the ARDS patient had large elevations of LTE4 levels compared with healthy subjects. When the HPLC fractions containing [3H]LTE4 and LT immunoreactivity in the ARDS sample were treated with acetic anhydride, HPLC analysis indicated that both radiolabel and immunoreactivity now eluted at the retention time of N-acetyl LTE4, the derivatized product of LTE4. The methods described are relatively easy and can be used to measure and validate the existence of peptidoleukotrienes in biological samples.
Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge.
Sulfidopeptide leukotrienes have been implicated in the pathogenesis of asthma because of their ability to induce bronchospasm, airways hyperreactivity, and increased mucus production. In the present study, the leukotrienes (LT) C4, D4, and E4 were measured in bronchoalveolar lavage fluid (BALF) before and 5 min after endobronchial allergen challenge in four subject groups: nonatopic nonasthmatic, nonatopic asthmatic, atopic nonasthmatic, and atopic asthmatic. As determined by high performance liquid chromatography (HPLC), after allergen challenge, the predominant sulfidopeptide leukotriene found in BALF from atopic asthmatics was LTC4. Smaller amounts of LTD4 and LTE4 were detectable. The baseline level of leukotrienes in the atopic asthmatics was 64 +/- 18 pg/ml, with measurable levels being found in nine of 11 samples. Atopic nonasthmatics had measurable levels in only one of seven baseline samples, whereas five of six nonatopic subjects had undetectable levels. Allergen challenge in atopic asthmatics resulted in significant increases in LTC4 over prechallenge levels (64 +/- 18 to 616 +/- 193 pg/ml) (p less than 0.01) and over levels in the three control groups after challenge (p = 0.0297). The atopic nonasthmatic group also had detectable leukotriene levels after allergen challenge (88 +/- 32 pg/ml), whereas leukotrienes remained undetectable in five of the six nonatopic samples. For comparison, histamine and the prostanoids prostaglandin D2 (PGD2) and thromboxane B2 (TxB2) were also measured in BALF. The levels of all three of these mediators increased in BALF from atopic asthmatics after allergen challenge. After allergen challenge, the best correlation was found between the levels in BALF for the prostanoids PGD2 and TxB2 (r = 0.88).(ABSTRACT TRUNCATED AT 250 WORDS)
Spectrum of prostanoid release after bronchoalveolar allergen challenge in atopic asthmatics and in control groups. An alteration in the ratio of bronchoconstrictive to bronchoprotective mediators.
Prostanoids have been implicated in the pathogenesis of asthma because of their potential role in the modulation of airway tone. In the present study, the bronchoconstrictors prostaglandin D2 (PGD2) and thromboxane (TX), and those prostanoids able to protect against bronchoconstriction, prostaglandin E2 (PGE2), and the stable metabolite of prostacyclin, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), were measured in bronchoalveolar lavage fluid (BALF) before and 5 min after endobronchial allergen challenge in four subject groups: nonatopic nonasthmatics (n = 6), nonatopic asthmatics (n = 3), atopic nonasthmatics (n = 9), and atopic asthmatics (n = 8). There were no significant differences in prechallenge prostanoid levels between the four groups, with the potentially bronchoprotective mediators present in highest concentration. Allergen challenge in atopic asthmatics resulted in significant increases (p less than 0.05) in PGD2 (97.4 +/- 19.4 to 1,053.2 +/- 338.6 pg/ml, mean +/- SEM) and TX (45.5 +/- 7.5 to 150.7 +/- 37.8 pg/ml) over prechallenge levels and control groups. Similarly, histamine increased in the atopic asthmatics after challenge (0.36 +/- 0.22 to 6.84 +/- 1.86 ng/ml; p less than 0.05). Atopic nonasthmatics had slight increases in PGD2 (96.9 +/- 25.4 to 219.7 +/- 47.5 pg/ml; p greater than 0.1) after challenge, whereas PGD2 and TX did not change in nonatopic subjects. A significant positive correlation was found between histamine, PGD2, and TX levels after challenge among all groups (p less than 0.001). There were no significant changes among the four groups after allergen challenge in 6-keto-PGF1 alpha or PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)
Activation of pulmonary mast cells by bronchoalveolar allergen challenge. In vivo release of histamine and tryptase in atopic subjects with and without asthma.
Human mast cells likely play a significant role in human asthma. In the present study, concentrations of tryptase and histamine in bronchoalveolar lavage fluid (BALF) were used as indicators of pulmonary mast cell activation. BALF was obtained before and after endobronchial allergen challenge and assessed for mediator content and cell composition in 4 subject groups: nonatopic nonasthmatics (Group 1, n = 7), nonatopic asthmatics (Group 2, n = 3), atopic nonasthmatics (Group 3, n = 7), and atopic asthmatics (Group 4, n = 7). Before challenge, histamine concentrations were not different between the 4 groups, whereas tryptase concentrations were significantly greater in the atopic asthmatics than in each of the other groups (p less than 0.04). Allergen challenge in atopic asthmatics resulted in significant increases above baseline in mean +/- SD histamine (0.7 +/- 7.1 to 2.8 +/- 2.0 ng/ml) and tryptase (2.0 +/- 1.7 to 10.1 +/- 8.2 ng/ml) concentrations in BALF (p less than 0.03). Atopic nonasthmatics also had increases above baseline in histamine (0.2 +/- 0.2 to 1.2 +/- 1.4 ng/ml) and tryptase (0.5 +/- 0.4 to 1.4 +/- 1.03 ng/ml) concentrations after allergen challenge (p less than 0.05). Though the histamine values were not significantly different between atopic nonasthmatics and atopic asthmatics after allergen challenge, tryptase concentrations were markedly higher in the atopic asthmatic group. The numbers, as well as the predominance of the T mast cell type in atopic asthmatics and nonasthmatics, were no different from controls. In nonatopic subjects, regardless of asthmatic state, histamine or tryptase concentrations were not altered by allergen challenge.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of lesions of the locus coeruleus complex on the circadian rhythm of plasma corticosterone in the mouse.
An apparently transient elevation of basal morning (08.00 h) plasma corticosterone levels in male mice was found 48 h after bilateral electrolytic lesions of the brainstem locus coeruleus complex but was not observed 6 weeks after lesioning.
Antileukotriene drugs in the management of asthma.
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Introduction. The immunobiology of leukotriene inhibitors.
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Leukotriene receptor antagonists and related compounds.
Leukotrienes (LTs), lipid mediators of inflammation, have proved to be important biochemicals involved in the symptoms and physiological changes of asthma. In the past year and a half, the development of three new drugs that modulate the LT pathway has been completed. The first subclass of these drugs, leukotriene receptor antagonists (LTRA) (zafirlukast and montelukast), blocks the interaction of the cysteinyl form of the LTs with the cell type bearing the receptor. The second subclass, the 5-lipoxygenase (5-LO) inhibitors (zileuton) inhibits the 5-LO enzyme, which prevents the formation of both cysteinyl LTs and LTB4. The LT modulators have shown efficacy in inhibiting the physiological changes occurring after allergen, acetylsalicylic acid and exercise challenge in asthmatics. In addition, they have shown efficacy in improving symptoms, beta-agonist use and forced expiratory volume in 1 s (FEV1) in chronic, 'day-to-day' asthma in patients with mild disease. Comparison studies with low doses of inhaled corticosteroids suggest that LT modulators may have similar effects on symptom scores and beta-agonist use, but have lesser effects on FEV1. Finally, emerging data suggest that these drugs are beneficial in decreasing the dose of inhaled corticosteroids necessary to control more moderate to severe asthma. While long term studies will be helpful in determining the 'disease modifying' effects of these drugs, data suggest that these drugs are useful in the treatment of a broad range of asthmatic patients.
Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma.
OBJECTIVE: To introduce and review zileuton, an orally active 5-lipoxygenase inhibitor that represents the first of a new class of medications to be used in the treatment of asthma. DATA SOURCES: A MEDLINE search (from 1966 to December 1995) was performed to identify pertinent English-language literature. STUDY SELECTION: Basic science studies on the pharmacokinetics of zileuton, its pathophysiologic effects on asthma, and clinical efficacy trials were reviewed. DATA EXTRACTION: Clinical trials were emphasized. Studies from ex vivo or animal models of pharmacologic and pharmacodynamic effects were considered for review where no in vivo human data were available. DATA SYNTHESIS: Zileuton has shown the ability to attenuate induced bronchospasm, produce some degree of bronchodilation, and provide antiinflammatory or steroid-sparing effects with both single doses (800 mg) and chronic treatment (400 and 600 mg qid). Zileuton has been studied in patients requiring daily inhaled beta-adrenergic agonist treatment; however, data from pediatric populations and comparisons with other asthma medications are limited at this time. Adverse effects include dyspepsia and elevated liver enzymes (incidence approximately 3%). One case of jaundice has been reported among the more than 5000 patients treated with zileuton. There is also some concern for drug interactions with hepatically cleared medications, such as theophylline. CONCLUSIONS: Zileuton represents the first drug of a new treatment category for asthma, the 5-lipoxygenase inhibitors. Some people with asthma may receive considerable benefit, but as it is an entirely new drug entity, zileuton's final place in the hierarchy of asthma medications remains to be determined.