BackgroundAsthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED.MethodsFuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13.ResultsFour phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was “mild, good lung function, early onset”, with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a “moderate, hyper-responsive, eosinophilic” phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a “mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic” phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a “severe uncontrolled, severe reversible obstruction, mixed granulocytic” phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort.ConclusionsFocusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies.Trial registration NCT01274507 (ADEPT), registered October 28, 2010 and NCT01982162 (U-BIOPRED), registered October 30, 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0482-9) contains supplementary material, which is available to authorized users.
Abstract. Schwann cells in culture divide in response to defined mitogens such as PDGF and glial growth factor (GGF), but proliferation is greatly enhanced if agents such as forskolin, which increases Schwann cell intracellular cAMP, are added at the same time as PDGF or GGF (Davis, J. B., and P. Stroobant. 1990. J. Cell Biol. 110:1353-1360. The effect of forskolin is probably due to an increase in numbers of PDGF receptors (Weinmaster, G., and G. Lemke. 1990. .Neuropeptides and/$-adrenergic agonists have been reported to have no effect on potentiating the mitogenic response of either PDGF or GGE We show that the neuropeptide calcitonin gene-related peptide (CGRP) increases Schwann cell cAMP levels, but the cells rapidly desensitize. We therefore stimulated the cells in pulsatile fashion to partly overcome the effects of desensitization and show that CGRP can synergize with PDGF to stimulate Schwann cell proliferation, and that CGRP is as effective as forskolin in the pulsatile regime.CGRP is a good substrate for the neutral endopeptidase 24.11. Schwann cells in vivo have this protease on their surface, so the action of CGRP could be terminated by this enzyme and desensitization prevented. We therefore suggest that CGRP may play an important role in stimulating Schwann cell proliferation by regulating the response of mitogenic factors such as PDGE T nEaE are two circumstances in which Schwann ceils, the glial cells of peripheral nerves, proliferate: during development and after nerve injury. During development, they proliferate as they migrate out along growing axons (Eccleston, 1992). After nerve injury, they undergo two waves of proliferation: one occurs acutely, adjacent to the injury site, whereas the second occurs over a prolonged period as the nerve undergoes Wallerian degeneration and regeneration and extends distally from the injury site (Fawcett and Keynes, 1990). Although it is still not clear how Schwann cell division is controlled in vivo, there has been considerable effort to identify the mitogens that regulate the proliferation of rat sciatic nerve Schwann cells in culture. PDGF, FGF-1 and FGF-2, TGF-/~, and glial growth factor (GGF) m have all been shown to promote the proliferation of these ceils. In addition, Schwann cells in culture respond to
Inflammation has been shown to play an important role in the mechanisms involved in the pathogenesis of hypertension. Connexins (Cxs)-based gap junction channels (GJCs) or hemichannels (HCs) are involved in the maintenance of homeostasis in the immune system. However, the role of Cx43-based channels in T-lymphocytes in mediating the immune response in essential hypertension is not fully understand. The present study was designed to investigate the role of Cxs-based channels in T lymphocytes in the regulation of hypertension-mediated inflammation. The surface expressions of T lymphocyte subtypes, Cx40/Cx43, and inflammatory cytokines (IFN-γ (interferon-gamma) and TNF-ɑ (tumor necrosis factor alpha)) in T cells, as well as gap junction communication of peripheral blood lymphocytes from essential hypertensive patients (EHs) and normotensive healthy subjects (NTs) were detected by flow cytometry. Expression levels and phosphorylation of Cx43 protein in peripheral blood lymphocytes of EHs and NTs were analyzed by Western blot. The proliferation rate of peripheral blood mononuclear cells (PBMCs) after treatment with a Cxs inhibitor was examined by a CCK-8 assay. The levels of inflammatory cytokines were detected using ELISA. Within the CD3+ T cell subsets, we found a significant trend toward an increase in the percentage of CD4+ T cells and CD4+/CD8+ ratio as well as in serum levels of IFN-γ and TNF-ɑ in the peripheral blood of EHs compared with those in NTs. Moreover, the peripheral blood lymphocytes of EH patients exhibited enhanced GJCs formation, increased Cx43 protein level and Cx43 phosphorylation at Ser368, and a significant increase in Cx40/Cx43 surface expressions levels in CD4+ or CD8+ T lymphocytes. Cx43-based channel inhibition by a mimetic peptide greatly reduced the exchange of dye between lymphocytes, proliferation of stimulated lymphocytes and the pro-inflammatory cytokine levels of EHs and NTs. Our data suggest that Cx40/Cx43-based channels in lymphocytes may be involved in the regulation of T lymphocyte proliferation and the production of pro-inflammatory cytokines, which contribute to the hypertensive inflammatory response.
NO is neither pre-stored nor packed in vesicles but is produced on demand. It then diffuses randomly from its site of production, being highly membrane-permeable. Endogenous NO is formed by the hydroxylation of Larginine to citrulline [14], a reaction catalysed by one of the three isoforms of NO synthase (NOS) [15]. Because NO has a short half-life (0.1±6 s) and is very reactive, NO physiology has largely been investigated indirectly by techniques that identify the distribution and activity of the NOS isoforms (Table 1). These distinct isoforms of NOS have been named after the cells in which they were ®rst isolated, puri®ed and cloned [15]. Each NOS isoform, i.e. endothelial (eNOS), neuronal (nNOS) and macrophage inducible (iNOS), varies considerably in subcellular location, structure, kinetics, regulation and function [15]. Each of the enzymes is a product of a unique gene, located on human chromosomes 7 (eNOS), 12 (nNOS) and 17 (iNOS) [15]. Both nNOS and eNOS are normal constituents of cells and are termed constitutive. The activity of both eNOS and nNOS is transient (minutes) and is triggered by Ca 2+ -elevating agonists [16]. In contrast, iNOS is not present in resting
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