National Jewish Health

About: National Jewish Health is a healthcare organization based out in Denver, Colorado, United States. It is known for research contribution in the topics: T cell & Asthma. The organization has 883 authors who have published 833 publications receiving 79201 citations. The organization is also known as: National Jewish Medical and Research Center.

Nocturnal asthma is associated with reduced glucocorticoid receptor binding affinity and decreased steroid responsiveness at night

Abstract: Background: The mechanisms for heightened nocturnal inflammation in patients with nocturnal asthma (NA) are not well understood. Objective: We sought to determine the glucocorticoid receptor (GR) characteristics and steroid responsiveness in subjects with NA. Methods: Eleven subjects with NA, 12 subjects with nonnocturnal asthma (NNA), and 16 nonasthmatic control subjects underwent blood sampling at 4 pm and 4 am in a random order separated by 1 week. GR binding affinity was measured in PBMCs by using a [ 3 H]-dexamethasone (DX) radioligand binding assay and Scatchard analysis. The capacity of hydrocortisone (HC) and DX to suppress proliferation of PBMCs stimulated with PHA was also determined. Results: The subjects with NA exhibited a significantly lower GR binding affinity at 4 am, detected by an elevated dissociation constant (Kd) of 22.2 ± 1.6 nmol/L compared with Kd at 4 pm (10.9 ± 0.7 nmol/L; P = .0001). The GR Kd of the NNA and control groups did not change significantly from 4 pm to 4 am. Within the NA group, there was also a significant inverse correlation between the absolute FEV 1 at 4 am and the Kd at 4 am ( r = –0.65, P = .04). PBMCs from subjects with NA exhibited less suppression of PBMC proliferation with HC and DX at 4 am compared with that at 4 pm ( P = .0004 and .03 for HC and DX, respectively). There were no circadian changes in suppression of PBMC proliferation in either the NNA or control groups. Conclusion: GR binding affinity and steroid responsiveness exhibit a circadian variation in subjects with NA, with a reduced GR binding affinity and suppression of PBMC proliferation at 4 am that is not observed in normal subjects or asthmatic subjects without nocturnal exacerbation. These observations may contribute to nocturnal airway inflammation by inhibiting the antiinflammatory effects of glucocorticoids. (J Allergy Clin Immunol 1999;103:66-71.)

Estrogen Determines Sex Differences in Airway Responsiveness after Allergen Exposure

Abstract: The female hormone estrogen is an important factor in the regulation of airway function and inflammation, and sex differences in the prevalence of asthma are well described. Using an animal model, we determined how sex differences may underlie the development of altered airway function in response to allergen exposure. We compared sex differences in the development of airway hyperresponsiveness (AHR) after allergen exposure exclusively via the airways. Ovalbumin (OVA) was administered by nebulization on 10 consecutive days in BALB/c mice. After methacholine challenge, significant AHR developed in male mice but not in female mice. Ovariectomized female mice showed significant AHR after 10-day OVA inhalation. ICI182,780, an estrogen antagonist, similarly enhanced airway responsiveness even when administered 1 hour before assay. In contrast, 17β-estradiol dose-dependently suppressed AHR in male mice. In all cases, airway responsiveness was inhibited by the administration of a neurokinin 1 receptor antagonist...

Cell surface expression of class II MHC proteins bound by a single peptide.

Abstract: On normal cells, the peptide-binding grooves of class II MHC proteins contain a wide spectrum of peptides. For some purposes, however, it would be helpful to have cells bearing class II proteins engaged by only one peptide species. In an attempt to make such cells we constructed a gene for a MHC class II beta-chain, IA beta b, covalently linked to a peptide, E alpha 52-68, which is known to bind to the peptide-binding groove of IAb. This gene, together with the gene for IA alpha b, was transfected into B lymphoma cells and fibroblasts. The IAb-E alpha complex was expressed on the surfaces of these cells where it could be recognized by a mAb and T cells specific for IAb plus E alpha 52-68. Most of the peptide on fibroblasts remained covalently attached to the IAb beta-chain, but the covalent linker and/or peptide were degraded to some extent on B lymphoma cells. Nearly all of the IAb expressed by transfected fibroblasts was occupied by the E alpha peptide. Of 16 IAb-reactive T cell hybridomas, only 3 could respond to the IAb-E alpha complex on fibroblasts, confirming the idea that recognition of MHC may often involve recognition of the peptides bound to the MHC as well.

Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity

Abstract: Bronchopulmonary dysplasia (BPD), a chronic lung disease affecting preterm neonates, is associated with significant childhood and adult health problems. Histopathologic features of BPD include impaired vascular and distal airway development. We previously showed that activation of hypoxia-inducible factors (HIFs) by inhibition of prolyl hydroxylase domain-containing proteins (PHDs) is feasible and that it stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis in vitro. We tested the hypothesis that enhancement of angiogenesis by activation of HIFs improves lung growth and function in prematurely born neonates in vivo. Preterm baboons (125 day+14 day pro re nata O2 model, corresponding to 27 human gestational weeks) were treated for 14 days with intravenous (i.v.) FG-4095, a PHD inhibitor. Notably, 77% of diminished total alveolar surface area in untreated controls was recovered by FG-4095 treatment. Functional significance of the structural changes was indicated by improved oxygenation and lung compliance in FG-4095-treated newborns. Surfactant proteins B and C and saturated phosphatidylcholine were unchanged. Incidence of spontaneous ductus arteriosus closure was increased, likely contributing to lower ratio of pulmonary to systemic blood flow in FG-4095 group. These findings indicate that HIF stimulation by PHD inhibition ameliorates pathological and physiological consequences of BPD.

In vitro activation of complement by isolated human heart subcellular membranes.

Abstract: Activation of human complement (C) occurred in vitro when mitochondrial membranes isolated from normal human heart tissue were incubated with normal human serum This activation, as measured by C3 depletion, was not completely inhibited by blocking classical pathway activity in serum treated with EGTA, in C2-deficient serum, or in C1-depleted serum, nor in serum heated at 50 degrees C for 30 min to block the alternative pathway, but it could be prevented by blocking the classical and the alternative pathway simultaneously with EDTA, or by treating heated serum (50 degrees C 30 min) with EGTA Factor B was converted in normal serum as well as in EGTA-treated serum, but not in EDTA-treated serum Mitochondrial membranes had no direct enzymatic or other activity that could inactivate functionally or highly purified C4 or C3, but the membranes could bind and activate C1 either in serum or in functionally pure C1 preparations C4 also bound to the mitochondrial membranes only in the presence of C1 These data suggest that the activation of C by heart subcellular membranes involved both the classical and the alternative pathways, that the mitochondrial membrane preparations were capable of forming stabel complexes with C1 and C4, but not C3, and that the mitochondrial membrane preparations did not contain enzymes or have inherent properties that could directly cause C3 conversion