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Biomedical subjects

J R Sheller

Publications and source records attributed to J R Sheller.

At least 19 recordsLinked to original sources
PubMed1996

A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings.

BACKGROUND: Segmental antigen challenge (SAC) and bronchoalveolar lavage (BAL) have been proven useful for investigating IgE-mediated lung inflammation in volunteers with allergies. OBJECTIVE: This model was used to evaluate the pulmonary antiinflammatory effects of an experimental 5-lipoxygenase inhibitor (zileuton) in subjects allergic to ragweed. We hypothesized that decreased generation of leukotrienes by inhibition of the 5-lipoxygenase pathway of arachidonic acid metabolism would diminish the subsequent inflammatory response resulting from antigen challenge. METHODS: Ten subjects with allergies received zileuton or placebo, 600 mg administered orally four times a day for 8 days, and then underwent bronchoscopy, BAL of a control segment, and SAC in the contralateral lung followed by BAL of the challenged segment 24 hours later in a double-blind, placebo-controlled, crossover protocol. Urinary excretion of leukotriene E4 induced by antigen challenge plus total and differential cell counts and the amount of total protein, albumin, urea, and eosinophil cationic protein in BAL fluid were determined. RESULTS: A significant inhibition of leukotriene production (approximately 86%) was observed in subjects receiving zileuton. In addition, there was a statistically significant increase in eosinophils after antigen challenge (0.6 +/- 0.2 x 10(4) eosinophils/ml increasing to 49.0 +/- 25.0 x 10(4) in subjects receiving placebo, whereas the influx of eosinophils in subjects receiving zileuton was not statistically different from baseline (1.1 +/- 0.7 x 10(4) eosinophils/ml increasing to 16.5 +/- 4.1 x 10(4); analysis of variance for repeated measures with post hoc comparisons). CONCLUSIONS: Treatment with zileuton altered the inflammatory response after antigen challenge. Products of the 5-lipoxygenase pathway appear to be important in recruiting eosinophils to the lung after SAC.

Adult↗
PubMed1995

Regional distribution of protease-resistant prion protein in fatal familial insomnia.

Protease-resistant prion protein, total prion protein, and glial fibrillary acidic protein were measured in various brain regions from 9 subjects with fatal familial insomnia. Six were homozygotes methionine/methionine at codon 129 (mean duration, 10.7 +/- 4 months) and 3 were heterozygotes methionine/valine (mean duration, 23 +/- 11 months). In all subjects, protease-resistant prion protein was detected in gray matter but not in white matter and peripheral organs. Its distribution was more widespread than that of the histopathological lesions, which were observed only in the presence of a critical amount of the abnormal protein. In the mediodorsal thalamic nucleus, however, a severe neuronal loss and astrogliosis were associated with relatively moderate amounts of protease-resistant prion protein, suggesting a higher vulnerability. There was no overall correlation between amount of protease-resistant prion protein and either glial fibrillary acidic protein or total prion protein. While protease-resistant prion protein was virtually limited to subcortical areas and showed a selective pattern of distribution in the subjects with disease of the shortest duration, it was more widespread in the subjects with a longer clinical course, indicating that with time the disease process spreads within the brain. The kinetics of the accumulation of protease-resistant prion protein varied among different brain regions: While in the neocortex and to a lesser extent in the limbic lobe and in the caudate nucleus, the amount increased with disease duration, in the mediodorsal thalamic nucleus and in the brainstem it was present in comparable amounts in all subjects regardless of the disease duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Flow volume loops in the evaluation of upper airway obstruction.

Patients with lesions that cause obstruction of the large airways are often misdiagnosed as having chronic lung disease or reactive airways disease. Close attention to the history and physical examination provides clues to the presence of a laryngeal or tracheal lesion. Obtaining a flow volume loop in the pulmonary function laboratory is a simple and effective method of noninvasively evaluating a patient for the presence of an upper airway obstruction. Fixed lesions cause plateaus in both the inspiratory and expiratory limbs of the flow volume loop. Variable intrathoracic lesions are characterized by expiratory slowing and flattening of the expiratory limb. An important caveat is that these changes may not be present in a patient with coexisting lower airway disease such as COPD or asthma. Variable extrathoracic lesions cause inspiratory slowing and a plateau on the inspiratory limb of the flow volume loop. Finally, the clinician should remember that the quality of the flow volume loop is totally dependent on the patient's effort and cooperation and, thus, that the tracings obtained in the pulmonary function laboratory may not have the classic shapes presented in this review.

Airway Obstruction↗
PubMed1994

Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene.

Leukotrienes constitute a class of potent biological mediators of inflammation and anaphylaxis (for reviews see refs 1 and 2). Their biosynthesis derives from 5-lipoxygenase-catalysed oxygenation of arachidonic acid in granulocytes, macrophages and mast cells. To examine the physiological importance of leukotrienes, we have disrupted the 5-lipoxygenase gene by homologous recombination in embryonic stem cells. 5-Lipoxygenase-deficient (5LX-/-) mice develop normally and are healthy. They show a selective opposition to certain inflammatory insults. Although there is no difference in their reaction to endotoxin shock, the 5LX-/- animals resist the lethal effects of shock induced by platelet-activating factor. Reaction to ear inflammation induced by phorbol ester is normal, whereas inflammation induced by arachidonic acid is markedly reduced. Contrasts were also found in two models of leukocyte chemotaxis in vivo. The phenotype of 5LX-/- mice under injurious insult identifies the role for leukotrienes in the pathophysiology of select inflammatory states.

Anaphylaxis↗
PubMed1994

Eicosanoids in bronchoalveolar lavage fluid of aspirin-intolerant patients with asthma after aspirin challenge.

We have recently shown that oral aspirin provocation leads to an increase in LTE4 and a reduction in 11-dehydro-TXB2 levels in urine of patients with aspirin induced-asthma (AIA). To test the hypothesis that cyclooxygenase inhibition and an enhancement of cysteinyl-leukotriene production occurs in the lungs of patients with AIA, we examined the eicosanoid levels in bronchoalveolar lavage fluid obtained 30 min after lysine-aspirin or placebo inhalation in 10 patients with AIA. Eosinophil cationic protein (ECP) levels were determined to evaluate eosinophil activation. Six asthmatics nonsensitive to aspirin (NA) underwent challenge with placebo. The dose of lysine-aspirin inhaled by patients with AIA was equal to that which had produced > or = 20% fall in FEV1. Compared with NA, patients with AIA had: (1) eicosanoid levels, particularly PGE2 and TXB2, elevated and (2) higher number of eosinophils and ECP. The overproduction of eicosanoids could be related to a distinct eosinophilic inflammation in airways of patients with AIA. Inhalation of lysine-aspirin had no effects on 12-HETE and 15-HETE levels, but it markedly depressed cyclooxygenase products and significantly enhanced leukotriene production in the lungs of patients with AIA.

Adult↗
PubMed1994

Effect of oral prednisone on airway inflammatory mediators in atopic asthma.

The mechanism of steroid action in asthma is unknown. Because steroids have effects in vitro on eicosanoid synthesis, we determined the effect of oral prednisone for 6 to 9 days on eicosanoid levels in bronchoalveolar lavage (BAL) fluid of 14 atopic asthmatic volunteers at baseline and after allergen instillation. We also determined the effect of prednisone on the ex vivo release of eicosanoids from macrophage-rich BAL-fluid cells. Prednisone reduced symptoms and inhaler use but had no significant effect on BAL-fluid eicosanoid levels. At baseline, prostaglandin D2 (PGD2) levels were 101 +/- 37 pg/ml in BAL fluid (mean +/- SEM), versus 66 +/- 18 pg/ml after prednisone; likewise, 5-hydroxy eicosatetraenoic acid (5-HETE) levels were 59 +/- 15 versus 78 +/- 21; leukotriene E4 (LTE4) levels were 35 +/- 13 versus 51 +/- 21, and 15-hydroxy eicosatetraenoic acid (15-HETE) levels were 29 +/- 8 versus 19 +/- 7. Allergen-stimulated levels of PGD2 were 1274 +/- 565 versus 1468 +/- 679 after prednisone; likewise, allergen-stimulated 5-HETE levels were 95 +/- 21 versus 82 +/- 21; those of LTE4 were 54 +/- 20 versus 91 +/- 51; and those of 15-HETE were 63 +/- 19 versus 60 +/- 25. Prednisone reduced the synthesis of eicosanoids in macrophage-rich BAL-fluid cells in vitro. LTB4 levels fell significantly from 35 +/- 6.4 ng/10(6) BAL-fluid cells to 17 +/- 5.4 after prednisone; likewise, levels of thromboxane B2 (TXB2) fell from 35.7 +/- 7.5 to 20.7 +/- 6.6. Part of the action of steroids may involve alteration in macrophage eicosanoid synthesis.

Administration, Oral↗
PubMed1994

New therapies for asthma.

Asthma is an inflammatory disease. Therefore, effective doses of antiinflammatory agents, particularly inhaled steroids, should have prominent place in the hierarchy of treatment, even in mild asthma. Suppression of airway inflammation may result in reduction of the need for bronchodilators, and perhaps the morbidity and mortality of asthma.

Aerosols↗
PubMed1993

Ethnic differences in response to morphine.

Only recently has attention been focused on the importance of interethnic differences as determinants of interindividual variability in drug response. We compared the pharmacokinetics and pharmacodynamics of morphine in eight Chinese and eight white healthy mean after 0.15 mg/kg of morphine intravenously. The clearance of morphine was significantly higher in the Chinese subjects than in the white subjects because of an increase in the partial metabolic clearance by glucuronidation. There was no interethnic difference in the metabolism to normorphine. Morphine depressed the respiratory response to rebreathing carbon dioxide more in white subjects than in Chinese subjects, resulting in a greater reduction in resting ventilation and resting end-tidal PCO2. The slope of the ventilation/PCO2 response curve, a measure of carbon dioxide sensitivity, was reduced more in white subjects than Chinese subjects. As a result, white subjects had a greater depression in ventilation at a PCO2 of 55 mm Hg. The morphine-induced reduction in blood pressure was also greater in white subjects than in Chinese subjects. Thus this study has shown ethnicity to be an important determinant of the disposition and effects of morphine.

Adult↗
PubMed1992

Thromboxane synthase inhibition in allergen challenged sheep lung: effect on eicosanoid synthesis.

We determined the effect of a novel inhibitor of thromboxane synthase, DP1904, on the baseline and allergen stimulated release of eicosanoids into the bronchoalveolar lavage fluid of sheep. DP1904 was effective in reducing the baseline and allergen stimulated production of TXB2. Inhibition of thromboxane synthase was associated with an increase in other prostaglandin endoperoxide metabolites, PGE2 and PGD2. Diversion of endoperoxide metabolism occurs in sheep lung tissue in vivo.

Allergens↗
PubMed1990

Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.

Therapeutic doses of glucocorticoids are thought to inhibit prostaglandin and leukotriene formation in humans. Several studies in animals, however, have failed to demonstrate modulation of eicosanoid biosynthesis by steroids in vivo. We administered prednisone (60 mg/day) to eight healthy volunteers and measured eicosanoid formation by a variety of cell types in vivo and ex vivo, using sensitive and specific physicochemical assays. We found that the in vivo course of prednisone failed to inhibit the synthesis of thromboxane A2, prostaglandin I2 (prostacyclin), prostaglandin E2, and leukotriene E4 in vivo and of leukotriene B4 ex vivo. Biosynthesis of leukotriene B4, thromboxane B2, and prostaglandins F2 and E2 by macrophage-rich bronchoalveolar lavage cells was strongly suppressed. These findings indicate that therapeutic regimens of glucocorticoids suppress eicosanoid biosynthesis in human macrophages but not in a number of other cell types with steroid receptors, the capacity for eicosanoid formation, and lipocortin-like material.

Adult↗
PubMed1990

Allergen-stimulated release of thromboxane A2 and leukotriene E4 in humans. Effect of indomethacin.

Allergen-stimulated release of a cyclooxygenase product (thromboxane [TX] A2) and a 5-lipoxygenase product (leukotriene [LT] E4) into the urine was measured in 10 atopic asthmatics undergoing allergen inhalation. Because indomethacin has been reported to increase allergic-stimulated 5-lipoxygenase product formation and to inhibit the late asthmatic response, we determined the effect of indomethacin (50 mg 3 times a day) or placebo on airway and biochemical responses to inhaled allergen in a randomized, blinded study. Urinary levels of the enzymatic metabolite of TXB2, 11-dehydro-TXB2, increased from 585 +/- 330 to 1,500 +/- 250 pg/mg creatinine (mean +/- SEM, p less than 0.05) 2 h after allergen. Urinary LTE4 increased from 190 +/- 37 to 1,100 +/- 400 (p less than 0.05) 2 h after challenge. The urinary levels of these eicosanoids were not elevated during the late response. Indomethacin significantly reduced urinary 11-dehydro-TXB2 levels without affecting the excretion of LTE4 or pulmonary function. Thus, we failed to obtain evidence for enhanced leukotriene formation during allergic stimulation in vivo in the presence of cyclooxygenase inhibition. Furthermore, we conclude that cyclooxygenase products are likely to play only a marginal role in allergic bronchoconstriction.

Adult↗
PubMed1990

Childhood pulmonary function following hyaline membrane disease.

Hyaline membrane disease per se is not associated with abnormal lung function or increased nonspecific airway reactivity in childhood or adulthood. Very-low-birth-weight infants who survive almost routinely in neonatal ICUs are at risk, however, for developing airflow obstruction and having airway hyperreactivity as children, and for having recurrent bouts of wheezing, cough, and respiratory infections. Neonates who develop BPD have the greatest risk of abnormal pulmonary function as children. Continued research into the prevention of premature birth and into the causes of neonatal lung injury, combined with improvements in the neonatal ICU and follow-up treatment, will undoubtedly contribute to improvement in the clinical course of premature infants.

Bronchial Provocation Tests↗
PubMed1989

Prematurity is associated with abnormal airway function in childhood.

To evaluate the long-term effect of prematurity and/or hyaline membrane disease (HMD) on pulmonary function and airway reactivity, we studied 49 prematurely born children aged 10 to 13 years. They were divided into three groups according to birth weight and HMD status: Groups I and II comprised the children weighing less than 1,500 g at birth, and Group III those whose birth weight exceeded 1,500 g. Children without HMD at birth were classified as Group I and those with HMD as Group II or III. We performed both pulmonary function tests and methacholine (MCh) challenges and compared the results with those of 27 age-matched controls born at term. We found that FEV1 and RV/TLC ratios were significantly different from control values in the groups with birth weights less than 1,500 g, regardless of their HMD status (Groups I and II). In Group I, results for FEF25-75%, Vmax50%, and DLCO were lower than those of controls. Airway reactivity was significantly increased in Groups I and II. A 20% drop in FEV1 after MCh challenge was found in 88%, 62%, 53%, and 36% of children in Groups I, II, and III and controls, respectively, and a 35% drop in SGaw occurred in 87%, 88%, 53%, and 59%. We conclude that prematurity and not HMD per se leads to long-term pulmonary abnormalities and to an increase in nonspecific airway reactivity.

Adolescent↗
PubMed1989

Airway responsiveness in isolated perfused rat lungs: effect of thoracic irradiation.

We developed techniques for assessing airway reactivity in isolated perfused rat lungs by measuring the lung mechanics changes produced by injection of ACh into the pulmonary circulation. Lung resistance (RL) and dynamic compliance (Cdyn) changed in a dose-response fashion after ACh. We used the preparation to examine the effect of thoracic irradiation on airway responsiveness and pulmonary inflammation. Groups of rats were studied after sham irradiation or 24 h or 72 h after a single dose of 1500 rads. Thoracic irradiation did not alter baseline lung mechanics, but did increase the responsiveness of rat lungs to ACh 72 h after radiation. Radiation was not associated with an increase in neutrophils in lung lavage, airways or peripheral lung tissue. We conclude that thoracic irradiation alters airways reactivity without causing overt pulmonary inflammation, and that isolated perfused lungs can be useful for measurement of airway reactivity.

Acetylcholine↗
PubMed1989

Postpneumonic empyema in childhood: selecting appropriate therapy.

In order to identify appropriate treatment options for postpneumonic empyema, we reviewed the medical records and, when possible, obtained long-term follow-up chest radiographs and pulmonary function tests on children treated for empyema during the past 11 years. Fifty-one patients were treated in various ways, with antibiotics alone (N = 10), or in combination with tube thoracostomy (N = 23) or decortication (N = 18). Despite administration of appropriate antibiotics and establishment of pleural drainage, many children required prolonged hospitalization and eventual decortication. Based on this review, a scoring system was developed allowing early classification by severity of pleural disease. Factors found to be predictors of severe pleural disease include (1) low pleural fluid pH or (2) glucose; (3) presence of moderate or severe scoliosis or (4) pleural peel or parenchymal entrapment by chest radiography; and (5) infection due to anaerobes, gram-negative organisms, or mycoplasma. Complete opacification of a hemithorax on chest radiography and a pleural peel to thoracic ratio greater than 40% were also associated with severe pleural disease. In patients with mild disease (N = 7), response to antibiotics alone, rapid resolution of fever, and shorter hospital stays were observed. In patients with more severe infections (moderate = 22, severe = 22), decortication accomplished earlier defervescence, radiographic improvement, and hospital discharge than simple tube thoracostomy. No deaths or morbidity were associated with decortication, which could often be accomplished through a minithoracotomy. Follow-up chest radiographs and pulmonary fuction tests showed a prompt return to normal after decortication. This experience indicates utility of a pleural disease severity scoring system in selection of treatment options for children with postpneumonic empyema.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Allergen-stimulated release of mediators into sheep bronchoalveolar lavage fluid. Effect of cyclooxygenase inhibition.

Products of arachidonic acid have been implicated as potential mediators of allergic airway responses in sheep and in humans. We therefore measured the release of arachidonate metabolites into sheep bronchoalveolar lavage fluid (BALF) after local instillation of Ascaris antigen, using a highly specific and sensitive approach, gas chromatography-negative ion-chemical ionization mass spectrometry. Allergen instillation caused increases in the levels of the potent bronchoconstrictors prostaglandin (PG) D2 and thromboxane (TX) A2 (as reflected by levels of TXB2) and of their enzymatic metabolites, 9 alpha, 11 beta-PGF2 and 11-dehydro-TXB2, respectively. Potential bronchodilators, PGI2 and PGE2, were also formed in increased amounts. Levels of the 5-lipoxygenase products, leukotriene (LT) B4 and C4, were not significantly increased. Pretreatment of sheep with cyclooxygenase inhibitors was associated with a decrease in the release of cyclooxygenase products and a concomitant increase in the allergen-stimulated release of LTB4 and LTC4. Eicosanoids are formed promptly in vivo in sheep after allergen instillation: inhibition of cyclooxygenase results in augmented generation of leukotrienes in the airways of sensitive sheep in response to antigen challenge.

Allergens↗