Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma.
ABSTRACT Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as "Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)." Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment.
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ABSTRACT: Asthma is characterized by airway hyper-responsiveness and variable airflow obstruction, in part as a consequence of hyper-contractile airway smooth muscle, which persists in primary cell culture. One potential mechanism for this hyper-contractility is abnormal intracellular Ca(2+) handling. We sought to compare intracellular Ca(2+) handling in airway smooth muscle cells from subjects with asthma compared to non-asthmatic controls by measuring: i) bradykinin-stimulated changes in inositol 1,4,5-trisphosphate (IP3) accumulation and intracellular Ca(2+) concentration, ii) sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) expression, iii) mechanisms of cytoplasmic Ca(2+) clearance assessed following instantaneous flash photolytic release of Ca(2+) into the cytoplasm. We found no differences in airway smooth muscle cell basal intracellular Ca(2+) concentrations, bradykinin-stimulated IP3 accumulation or intracellular Ca(2+) responses. Quantification of SERCA2 mRNA or protein expression levels revealed no differences in ASM cells obtained from subjects with asthma compared to non-asthmatic controls. We did not identify differences in intracellular calcium kinetics assessed by flash photolysis and calcium uncaging independent of agonist-activation with or without SERCA inhibition. However, we did observe some correlations in subjects with asthma between lung function and the different cellular measurements of intracellular Ca(2+) handling, with poorer lung function related to increased rate of recovery following flash photolytic elevation of cytoplasmic Ca(2+) concentration. Taken together, the experimental results reported in this study do not demonstrate major fundamental differences in Ca(2+) handling between airway smooth muscle cells from non-asthmatic and asthmatic subjects. Therefore, increased contraction of airway smooth muscle cells derived from asthmatic subjects cannot be fully explained by altered Ca(2+) homeostasis.BMC Pulmonary Medicine 12/2015; 15(1):9. DOI:10.1186/s12890-015-0009-z · 2.49 Impact Factor
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ABSTRACT: The endoplasmic reticulum (ER) is a specialized organelle that plays a central role in biosynthesis, correct protein folding, and posttranslational modifications of secretory and membrane proteins. Loss of homeostasis in ER functions triggers the ER stress response, resulting in activation of unfolded protein response (UPR), a hallmark of many inflammatory diseases. These pathways have been reported as critical players in the pathogenesis of various pulmonary disorders, including pulmonary fibrosis, lung injury, and chronic airway disorders. More interestingly, ER stress and the related signaling networks are emerging as important modulators of inflammatory and immune responses in the development of allergen-induced bronchial asthma, especially severe asthma.Allergy, asthma & immunology research 03/2015; 7(2):106-17. DOI:10.4168/aair.2015.7.2.106 · 3.08 Impact Factor
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ABSTRACT: Interleukin-27 (IL-27) is a multifunctional cytokine with both pro-inflammatory and immunoregulatory functions. At present, the role of IL-27 in pulmonary fibrosis remains unknown. In this study, we observed the expression of IL-27/IL-27R in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. We verified the role of IL-27 using hematoxylin and eosin as well as Masson's staining methods and measuring the content of hydroxyproline as well as collagen I and III. We assessed the differentiation of T lymphocytes in the spleen and measured the concentration of cytokines in bronchoalveolar lavage fluid (BALF) and the expression level of relevant proteins in the JAK/STAT and TGF-ß/Smad signaling pathways in lung tissue. Increased IL-27 expression in BLM-induced pulmonary fibrosis was noted. IL-27 treatment may alleviate pulmonary fibrosis and increase the survival of mice. IL-27 inhibited the development of CD4(+) IL-17(+), CD4(+) IL-4(+) T, and CD4(+) Foxp3(+) cells and the secretion of IL-17, IL-4, IL-6, and TGF-ß. IL-27 induced the production of CD4(+) IL-10(+) and CD4(+) INF-γ(+) T cells. IL-27 decreased the levels of phosphorylated STAT1, STAT3, STAT5, Smad1, and Smad3 but increased the level of SOCS3. This study demonstrates that IL-27 potentially attenuates BLM-induced pulmonary fibrosis by regulating Th17 differentiation and cytokine secretion.BMC Pulmonary Medicine 12/2015; 15(1). DOI:10.1186/s12890-015-0012-4 · 2.49 Impact Factor