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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
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↗
PubMed1989

Thromboxane biosynthesis in allergen-induced bronchospasm. Evidence for platelet activation.

To determine if platelet activation occurs after allergen inhalation in atopic asthmatics, we measured two urinary metabolites of the principal cyclooxygenase product of platelets, thromboxane A2 (TxA2), using the sensitive and specific technique of gas chromatography-negative ion, chemical ionization-mass spectrometry. Seven atopic asthmatics underwent allergen challenge after low dose aspirin to suppress platelet thromboxane generation and on placebo days. On placebo days, the urinary levels of 2,3-dinor-TxB2 increased from 76 +/- 22 pg/mg creatinine to 216 +/- 95 after allergen, and 11-dehydro-TxB2 from 396 +/- 98 to 627 +/- 137 (p less than 0.05). Low dose aspirin suppressed excretion of urinary thromboxane metabolites and prevented the rise after allergen inhalation without altering the bronchoconstriction. Excretion of 2,3-dinor-6-keto-PGF1 alpha, a metabolite of prostacyclin, was unaltered by this aspirin regimen. We conclude that platelets are activated after allergen challenge, but that platelet-derived TxA2 is not important in the early bronchoconstrictor response.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Pulmonary function in long-term survivors of hyaline membrane disease.

In order to determine the long-term pulmonary consequences of hyaline membrane disease (HMD), we measured pulmonary function and airway responsiveness to methacholine in 22 survivors of HMD aged 18 to 22 years. Nineteen age-matched control subjects without a history of lung disease or asthma were also studied. There was no statistically significant difference between the mean pulmonary function test results of the control vs the HMD group. The mean N2 delta of the five HMD patients who required assisted ventilation was significantly different from that of the control group. Airway responsiveness to methacholine, as estimated by the dose of methacholine aerosol necessary to provoke a 35 percent fall in SGaw did not differ between the control and HMD groups. In the absence of prematurity, low birth weight (less than 1,500 g), and requirement for positive pressure ventilation, HMD is not associated with an increase in nonspecific airway reactivity or abnormal pulmonary function in adulthood.

Adolescent↗
PubMed1987

Right ventricular hypertrophy is an important determinant of right ventricular infarction complicating acute inferior left ventricular infarction.

To explore the role of right ventricular hypertrophy and chronic obstructive pulmonary disease in the pathogenesis of right ventricular infarction, 27 consecutive patients with a first inferior left ventricular infarction were prospectively studied. Right ventricular infarction was diagnosed using established hemodynamic criteria. Right ventricular hypertrophy was defined as right ventricular free wall thickness greater than or equal to 5 mm. Patients were classified into two groups: Group I patients with right ventricular infarction (n = 15), and Group II patients without right ventricular infarction (n = 12). The ratio of forced expiratory volume over forced vital capacity (FEV1/FVC) and forced expiratory flow between 25 and 75% expired volume (FEF) as a percent of predicted values were significantly reduced in Group I versus Group II (90 +/- 5 versus 105 +/- 6% and 63 +/- 13 versus 103 +/- 15%, respectively; p less than 0.05). This was associated with increased right ventricular wall thickness (Group I 5.5 +/- 0.3 mm versus Group II 3.9 +/- 0.2 mm, p less than 0.001). Multiple logistic regression analysis demonstrated that right ventricular wall thickness was the strongest predictor of right ventricular infarction (p less than 0.0005). No significant difference was found in the site of right coronary occlusion, collateral blood supply or extent of coronary artery disease between the two groups. These findings suggest that right ventricular hypertrophy predisposes patients with acute inferior myocardial infarction to right ventricular infarction independent of the site or extent of coronary artery disease.

Adult↗
PubMed1987

(5Z,13E)-(15S)-9 alpha,11 beta,15-trihydroxyprosta-5,13-dien-1-oic acid (9 alpha,11 beta-prostaglandin F2): formation and metabolism by human lung and contractile effects on human bronchial smooth muscle.

Prostaglandin D2 (PGD2) was recently found to be stereospecifically converted to the compound (5Z,13E)-(15S)-9 alpha,11 beta,15-trihydroxyprosta-5,13-dien-1-oic acid (9 alpha,11 beta-PGF2) by a human liver cytosolic NADPH-dependent 11-ketoreductase enzyme. Because PGD2 is a potent bronchoconstrictor and is released into bronchoalveolar lavage fluid after allergen stimulation in patients with allergic asthma, the ability of human lung to metabolize PGD2 to 9 alpha,11 beta-PGF2 and the contractile effects of 9 alpha,11 beta-PGF2 on human bronchial smooth muscle were investigated. The 100,000 X g supernatant of human lung converted PGD2 in the presence of an NADPH-generating system stereospecifically to 9 alpha,11 beta-PGF2 at a rate of 3.46 +/- 0.94 pmol per min per mg of protein. 9 alpha,11 beta-PGF2 was found to contract human bronchial rings in a dose-dependent fashion with a potency virtually identical with that of both PGD2 and PGF2 alpha, known potent bronchial constrictors. PGD2 was found to be a very poor substrate for human lung 15-hydroxyprostaglandin dehydrogenases and to be preferentially metabolized by lung to 9 alpha,11 beta-PGF2. 9 alpha,11 beta-PGF2 was also found to be a very poor substrate for the lung 15-hydroxyprostaglandin dehydrogenases. Thus, once formed, 9 alpha,11 beta-PGF2 would not be expected to be rapidly inactivated in situ by these metabolic enzymes. These results suggest that 9 alpha,11 beta-PGF2 may participate along with other putative mediators in the pulmonary allergic response in humans.

Bronchi↗
PubMed1987

Asthma: emerging concepts and potential therapies.

Asthma is a disease of the airways that results in reversible airflow obstruction. Recent investigations have suggested that airway inflammation is associated with increased airway responsiveness and worsening of asthmatic symptoms. The role that mast cell mediators might play in the production of asthma has been investigated by use of newer analytical techniques and by use of fiberoptic bronchoscopy with lavage to obtain lower respiratory tract fluid and cells. In addition, new investigational compounds that interfere with the synthesis or action of inflammatory mediators have been tested. Developing lines of investigation suggest that chronic activation of inflammatory cells may be important in the pathogenesis of asthma.

Adolescent↗
PubMed1987

Acute effects of thoracic irradiation on lung function and structure in awake sheep.

To investigate the acute physiological and structural changes after lung irradiation, the effects of whole-lung irradiation were investigated in fourteen sheep. Ten sheep were prepared with vascular and chronic lung lymph catheters, then a week later were given 1,500 rad whole-lung radiation and monitored for 2 days. Four sheep were given the same dose of radiation and were killed 4 h later for structural studies. Lung lymph flow increased at 3 h after radiation (14.6 +/- 2.1 ml/h) to twice the base-line flow rate (7.5 +/- 1.3), with a high lymph-to-plasma protein concentration. Pulmonary arterial pressure increased twofold from base line (18 +/- 1.6 cmH2O) at 2 h after radiation (33 +/- 3.8). Cardiac output and systemic pressure in the aorta did not change after lung radiation. Arterial O2 tension decreased from 85 +/- 3 to 59 +/- 4 Torr at 1 day after radiation. Lymphocyte counts in both blood and lung lymph decreased to a nadir by 4 h and remained low. Thromboxane B2 concentration in lung lymph increased from base line (0.07 +/- 0.03 ng/ml) to peak at 3 h after radiation (8.2 +/- 3.7 ng/ml). The structural studies showed numerous damaged lymphocytes in the peripheral lung and bronchial associated lymphoid tissue. Quantitative analysis of the number of granulocytes in peripheral lung showed no significant change (base line 6.2 +/- 0.8 granulocytes/100 alveoli, 4 h = 10.3 +/- 2.3). The most striking change involved lung airways. The epithelial lining of the majority of airways from intrapulmonary bronchus to respiratory bronchiolus revealed damage with the appearance of intracellular and intercellular cell fragments and granules. This new large animal model of acute radiation lung injury can be used to monitor physiological, biochemical, and morphological changes after lung radiation. It is relevant to the investigation of diffuse oxidant lung injury as well as to radiobiology per se.

Animals↗