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.

Role of IL-18 in second-hand smoke-induced emphysema.

Abstract: Chronic second-hand smoke (SHS) exposure comprises the main risk factor for nonsmokers to develop chronic obstructive pulmonary disease (COPD). However, the mechanisms behind the chronic inflammation and lung destruction remain incompletely understood. In this study, we show that chronic exposure of Sprague-Dawley rats to SHS results in a significant increase of proinflammatory cytokine IL-18 and chemokine (C-C motif) ligand 5 in the bronchoalveolar lavage fluid (BALF) and a significant decrease of vascular endothelial growth factor (VEGF) in the lung tissue. SHS exposure resulted in progressive alveolar airspace enlargement, cell death, pulmonary vessel loss, vessel muscularization, collagen deposition, and right ventricular hypertrophy. Alveolar macrophages displayed a foamy phenotype and a decreased expression of the natural inhibitor of IL-18, namely, IL-18 binding protein (IL-18BP). Moreover, IL-18 down-regulated the expression of VEGF receptor-1 and VEGFR receptor-2, and induced apoptosis in pulmonary microvascular endothelial cells in vitro. We also observed a trend toward increased concentrations of IL-18 in the BALF of patients with COPD. Our findings suggest that IL-18-mediated endothelial cell death may contribute to vascular destruction and disappearance in SHS-induced COPD. Moreover, IL-18 and IL-18BP are potential new targets for therapeutics.

Impact of Age and Sex on Response to Asthma Therapy

Abstract: Rationale: Age and sex are associated with differences in asthma prevalence and morbidity.Objectives: To determine if age and sex associate with distinct phenotypes and a variable response to therapy in subjects with mild to moderate asthma.Methods: We used Asthma Clinical Research Network data to determine the impact of age and sex on phenotypes and treatment failures among subjects participating in 10 trials from 1993 to 2003.Measurements and Main Results: A total of 1,200 subjects were identified (median age, 30.4 yr; male, 520 [43.3%]; female, 680 [56.7%]) and analyzed. A higher proportion of subjects greater than or equal to 30 years old experienced treatment failures (17.3% vs. 10.3%; odds ratio [OR], 1.82; confidence interval [CI], 1.30–2.54; P < 0.001), and rates increased proportionally with increasing age older than 30 across the cohort (OR per yr, 1.02 [CI, 1.01–1.04]; OR per 5 yr, 1.13 [CI, 1.04–1.22]; P < 0.001). Lower lung function and longer duration of asthma were associated with a higher ...

Risk factors for symptom onset in PI*Z alpha-1 antitrypsin deficiency.

Abstract: BACKGROUND In an early study of highly symptomatic patients with PI*Z alpha-1 antitrypsin deficiency (AAT), tobacco smoking was identified as a risk factor by comparing the age of symptom onset in smokers and nonsmokers. Age of symptom onset has not been well studied in relationship to other environmental exposures. METHODS Environmental exposures were assessed in 313 PI*Z adults through retrospective self-administered questionnaire. Age of onset of symptoms with and without these exposures were analyzed through survival analysis. RESULTS Personal smoking was the most important risk factor, associated with earlier onset of cough and wheeze, and showed a dose-dependent relationship with the onset of dyspnea. Childhood environmental tobacco smoke (ETS) exposure was independently associated with younger age of onset of cough. Earlier onset of wheeze was also associated with childhood respiratory infections and family history of emphysema. The report of childhood respiratory infections was associated with childhood ETS exposure, but no statistically significant interactions were noted. CONCLUSIONS We conclude that both personal and secondhand exposure to tobacco smoke in childhood are likely to accelerate the onset of symptoms in AAT deficient patients. Respiratory infections in childhood may also contribute to this risk.

Functional thrombin receptors on human T lymphoblastoid cells.

Abstract: Human alpha-thrombin stimulated five different T lymphoblastoid cell lines to increase intracellular free Ca2+ concentrations, whereas five B cell lines did not similarly respond. The T cell intracellular free Ca2+ increased rapidly, plateaued within 10 to 20 s, and then declined without any measurable sustained intracellular free Ca2+ elevation. Liberation of inositol trisphosphate peaked within 60 s, and a rapid and sustained activation of protein kinase C was induced. The thrombin-specific inhibitor, hirudin, completely blocked the response to alpha-thrombin. Catalytically inactivated forms of alpha-thrombin failed to stimulate the T cells, whereas trypsin, gamma-thrombin (which lacks fibrinogen clotting activity), or the synthetic 14-amino acid thrombin receptor-activation peptide stimulated T cells, but required approximately 10-, approximately 15-, or approximately 100-fold higher concentrations, respectively, when compared to alpha-thrombin. Stimulation by thrombin receptor-activation peptide was desensitized by alpha-thrombin, and vice versa, but alpha-thrombin did not desensitize stimulation by mAb to the TCR/CD3 Ag. The presence of the receptor on T but not on B cells was confirmed by flow-cytometric analysis using a mAb against the human thrombin receptor. These findings demonstrate functional thrombin receptors on T lymphoblastoid cells that may be capable of activating the cells, independently of an ongoing immune response.

Critical Role of the Fc Receptor γ-Chain on APCs in the Development of Allergen-Induced Airway Hyperresponsiveness and Inflammation

Abstract: The FcR common γ-chain (FcRγ) is an essential component of the receptors FceRI, FcγRI, and FcγRIII, which are expressed on many inflammatory cell types. The role of these receptors in the initiation or maintenance of allergic inflammation has not been well defined. FcRγ-deficient (FcRγ−/−) and control (wild-type (WT)) mice were sensitized and subsequently challenged with OVA. Following sensitization and challenge to OVA, FcRγ-deficient (FcRγ−/−) mice developed comparable levels of IgE and IgG1 as WT mice. However, numbers of eosinophils, levels of IL-5, IL-13, and eotaxin in bronchoalveolar lavage fluid, and mononuclear cell (MNC) proliferative responses to OVA were significantly reduced, as was airway hyperresponsiveness (AHR) to inhaled methacholine. Reconstitution of FcRγ−/− mice with whole spleen MNC from WT mice before sensitization restored development of AHR and the numbers of eosinophils in bronchoalveolar lavage fluid; reconstitution after sensitization but before OVA challenge only partially restored these responses. These responses were also restored when FcRγ−/− mice received T cell-depleted MNC, T and B cell-depleted MNC, or bone marrow-derived dendritic cells before sensitization from FcR+/+ or FcγRIII-deficient but not FcRγ−/− mice. The expression levels of FcγRIV on bone marrow-derived dendritic cells from FcR+/+ mice were found to be low. These results demonstrate that expression of FcRγ, most likely FcγRI, on APCs is important during the sensitization phase for the development of allergic airway inflammation and AHR.