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    ABSTRACT: The understanding of interleukin-1 (IL-1) family cytokines in inflammatory disease has rapidly developed, due in part to the discovery and characterization of inflammasomes, which are multi-subunit intracellular protein scaffolds principally enabling recognition of a myriad of cellular stimuli, leading to the activation of caspase-1 and the processing of IL-1β and IL-18. Studies continue to elucidate the role of inflammasomes in immune responses induced by both microbes and environmental factors. This review focuses on the current understanding of inflammasome activity in the lung, with particular focus on the non-microbial instigators of inflammasome activation, including inhaled antigens, oxidants, cigarette smoke, diesel exhaust particles, mineral fibers, and engineered nanomaterials, as well as exposure to trauma and pre-existing inflammatory conditions such as metabolic syndrome. Inflammasome activity in these sterile inflammatory states contribute to diseases including asthma, chronic obstructive disease, acute lung injury, ventilator-induced lung injury, pulmonary fibrosis, and lung cancer.
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    ABSTRACT: Vitamin D deficiency (VDD) is highly prevlalent worldwide. The classical role for vitamin D is to regulate calcium absorption form the gastrointestinal tract and influence bone health. Recently vitamin D receptors and vitamin D metabolic enzymes have been discovered in numerous sites systemically supporting diverse extra-skeletal roles of vitamin D, for example in asthmatic disease. Further, VDD and asthma share several common risk factors including high latitude, winter season, industrialization, poor diet, obesity, and dark skin pigmentation. Vitamin D has been demonstrated to possess potent immunomodulatory effects, including effects on T cells and B cells as well as increasing production of antimicrobial peptides (e.g. cathelicidin). This immunomodulation may lead to asthma specific clinical benefits in terms of decreased bacterial/viral infections, altered airway smooth muscle-remodeling and -function as well as modulation of response to standard anti-asthma therapy (e.g. glucocorticoids and immunotherapy). Thus, vitamin D and its deficiency have a number of biological effects that are potentially important in altering the course of disease pathogenesis and severity in asthma. The purpose of this first of a two-part review is to review potential mechanisms whereby altering vitamin D status may influence asthmatic disease. Copyright © 2015. Published by Elsevier Ltd.
    Pulmonary Pharmacology &amp Therapeutics 02/2015; DOI:10.1016/j.pupt.2015.02.004 · 2.54 Impact Factor
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    ABSTRACT: A small population of patients with severe asthma does not respond to glucocorticoids (steroid resistant [SR]). They have high morbidity, highlighting an urgent need for strategies to enhance glucocorticoid responsiveness. We investigated the immunologic differences between steroid-sensitive (SS) and SR asthmatic patients and the effect on immunophenotype of oral calcitriol treatment because it has been previously shown to beneficially modulate the clinical response to glucocorticoids in patients with SR asthma. CD8-depleted PBMCs were isolated from 12 patients with SS and 23 patients with SR asthma and cultured for 7 days with anti-CD3 and IL-2 with or without dexamethasone. Cytokine production was assessed in supernatants by using the Cytometric Bead Array. Patients with SR asthma were subsequently randomized to oral calcitriol or placebo therapy, and identical studies were repeated. Patients with SR asthma produced significantly increased IL-17A and IFN-γ levels compared with those in patients with SS asthma, although it was evident that cells from individual patients might overproduce one or the other of these cytokines. Production of IL-17A was inversely and production of IL-13 was positively associated with the clinical response to prednisolone. Oral calcitriol, compared with placebo, therapy of the patients with SR asthma significantly improved dexamethasone-induced IL-10 production in vitro while suppressing dexamethasone-induced IL-17A production. This effect mirrored the previously demonstrated improvement in clinical response to oral glucocorticoids in calcitriol-treated patients with SR asthma. IL-17A(high) and IFN-γ(high) immunophenotypes exist in patients with SR asthma. These data identify immunologic pathways that likely underpin the beneficial clinical effects of calcitriol in patients with SR asthma by directing the SR cytokine profile toward a more SS immune phenotype, suggesting strategies for identifying vitamin D responder immunophenotypes. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.