Degradation of Monocyte Chemoattractant Protein-1 by Tryptase Co-Released in Immunoglobulin E-Dependent Activation of Primary Human Cultured Mast Cells.
Int Arch Allergy Immunol. 2018 Jul 18;:1-8
Authors: Tam IYS, Ng CW, Lau HYA, Tam SY
BACKGROUND: Mast cells are key immune effector cells which release chemokines, proteases, and other inflammatory mediators upon activation by immunological stimuli. The aim of this study was to investigate the effects of co-releasing proteases on the kinetics of release of the chemokine monocyte chemoattractant protein-1 (MCP-1) in immunoglobulin E (IgE)-mediated activation of human mast cells.
METHODS: Homogenous populations of mature and functional primary human mast cells were generated from CD34+ progenitors originated from buffy coats of healthy adult donors. The releases of MCP-1 from human mast cells in basal conditions and in response to FcεRI cross-linking were assessed at different time points. The effects of different types of protease inhibitors on MCP-1 release from these mast cells under stimulated or unstimulated conditions were also investigated.
RESULTS: Cultured human mast cells released MCP-1 in basal conditions and its levels increased in a time-dependent manner. When stimulated by FcεRI cross-linking, the levels of MCP-1 detected in the medium gradually decreased over time after the initial peak induction. Such a decline in MCP-1 levels after IgE-dependent activation was completely prevented by pretreatment with a cocktail of protease inhibitors or the specific tryptase inhibitor APC366.
CONCLUSIONS: Direct regulation of MCP-1 expression by co-release of tryptase in cultured human mast cells upon IgE-dependent activation demonstrates a role of the serglycin:serine protease axis in modulation of inflammatory reactions through proteolytic degradation of mediators such as chemokines.
PMID: 30021208 [PubMed - as supplied by publisher]
Predictors of benefit from high-altitude climate therapy in adults with severe asthma.
Neth J Med. 2018 Jul;76(5):218-225
Authors: Hashimoto S, Rijssenbeek-Nouwens LH, Fieten KB, Weersink EJ, Bel EH
BACKGROUND: High-altitude climate therapy has been shown to benefit patients with severe asthma but it is not known which patients benefit most from this treatment. In the current study we aimed to identify clinical, functional and inflammatory predictors of favourable outcome of high-altitude climate therapy.
METHODS: This is a secondary analysis of a prospective cohort including 136 adult patients with a diagnosis of severe refractory asthma, referred to the Dutch Asthma Centre in Davos (1600 metres above sea level), Switzerland. They had assessments of medication usage, asthma-related quality of life (Asthma-related Quality of Life Questionnaire, AQLQ), asthma control, body mass index (BMI), sino-nasal symptoms, fatigue, lung function (forced expiratory volume in one second, FEV1), exercise tolerance, allergy and inflammation (fraction of exhaled nitric oxide, blood eosinophils) at entry and after 12 weeks of treatment. Five clinically relevant outcomes were considered: AQLQ, oral corticosteroid dose, FEV1, body mass index and blood eosinophils. Independent predictors of beneficial outcome were identified by multiple linear regression analysis.
RESULTS: Lower blood eosinophil counts (p < 0.01), younger age (p = 0.02) and poorer asthma control (p < 0.01) were independently associated with greater reduction in the dose of oral corticosteroids. Lower fatigue score at baseline (p = 0.01) was associated with greater weight loss (reduction in BMI). Higher levels of total IgE at baseline (p < 0.01), and higher doses of inhaled corticosteroids (p = 0.03) were associated with greater decreases in blood eosinophils. There were no predictors for improvement in AQLQ or FEV1.
CONCLUSIONS: The beneficial effect of high-altitude climate therapy in adults with severe asthma can be predicted by patient characteristics, such as age, blood eosinophils and degree of asthma control before admission.
PMID: 30019677 [PubMed - in process]
Continuous Inhalation Exposure to Fungal Allergen Particulates Induces Lung Inflammation While Reducing Innate Immune Molecule Expression in the Brainstem.
ASN Neuro. 2018 Jan-Dec;10:1759091418782304
Authors: Peng X, Madany AM, Jang JC, Valdez JM, Rivas Z, Burr AC, Grinberg YY, Nordgren TM, Nair MG, Cocker D, Carson MJ, Lo DD
Continuous exposure to aerosolized fine (particle size ≤2.5 µm) and ultrafine (particle size ≤0.1 µm) particulates can trigger innate inflammatory responses in the lung and brain depending on particle composition. Most studies of manmade toxicants use inhalation exposure routes, whereas most studies of allergens use soluble solutions administered via intranasal or injection routes. Here, we tested whether continuous inhalation exposure to aerosolized Alternaria alternata particulates (a common fungal allergen associated with asthma) would induce innate inflammatory responses in the lung and brain. By designing a new environmental chamber able to control particle size distribution and mass concentration, we continuously exposed adult mice to aerosolized ultrafine Alternaria particulates for 96 hr. Despite induction of innate immune responses in the lung, induction of innate immune responses in whole brain samples was not detected by quantitative polymerase chain reaction or flow cytometry. However, exposure did trigger decreases in Arginase 1, inducible nitric oxide synthase, and tumor necrosis factor alpha mRNA in the brainstem samples containing the central nervous system respiratory circuit (the dorsal respiratory group, ventral respiratory group, and the pre-Bötzinger and Bötzinger complexes). In addition, a significant decrease in the percentage of Toll-like receptor 2-expressing brainstem microglia was detected by flow cytometry. Histologic analysis revealed a significant decrease in Iba1 but not glial fibrillary acidic protein immunoreactivity in both the brainstem and the hippocampus. Together these data indicate that inhalation exposure to a natural fungal allergen under conditions sufficient to induce lung inflammation surprisingly causes reductions in baseline expression of select innate immune molecules (similar to that observed during endotoxin tolerance) in the region of the central nervous system controlling respiration.
PMID: 30016877 [PubMed - in process]
Circulating Clusterin and Osteopontin Levels in Asthma and Asthmatic Pregnancy.
Can Respir J. 2017;2017:1602039
Authors: Dombai B, Ivancsó I, Bikov A, Oroszi D, Bohács A, Müller V, Rigó J, Vásárhelyi B, Losonczy G, Tamási L
Asthma in pregnancy poses a risk of adverse outcomes. Osteopontin and clusterin emerged as asthma biomarkers; however, their circulating levels during pregnancy are unknown yet. This cross-sectional study investigated peripheral osteopontin and clusterin levels and their relationship to disease control in 26 asthmatic pregnant (AP), 22 asthmatic nonpregnant (ANP), and 25 healthy pregnant (HP) women and 12 healthy controls (HNP). Osteopontin levels of ANP and HNP were similar (2.142 [1.483-2.701] versus 2.075 [1.680-2.331] ng/mL, p = 0.7331). Pregnancy caused a marked elevation in both healthy (HP: 3.037 [2.439-4.015] ng/ml, p = 0.003 versus HNP) and asthmatic (AP: 2.693 [1.581-3.620] ng/ml) patients; thus the pregnant groups did not differ (p = 0.3541). Circulating clusterin levels were comparable in ANP and HNP (109.2 [95.59-116.3] versus 108.8 [97.94-115.3] µg/mL, p = 0.8730) and the level was lower in HP (98.80 [84.26-105.5] µg/mL, p = 0.0344 versus HNP). In contrast, the level was higher in AP (111.7 [98.84-125.6] µg/mL, p = 0.0091 versus HP). In ANP, a positive correlation of PEF (r = 0.3405; p = 0.0221) and a negative correlation of Raw (r = -0.3723; p = 0.0128) to clusterin level were detected. Circulating osteopontin level increases in pregnancy regardless of concomitant well-controlled asthma, indicating its gestational role. Clusterin level decreases in healthy but not in asthmatic pregnancy and correlates directly with lung function.
PMID: 29200898 [PubMed - indexed for MEDLINE]
Is insomnia a risk factor for new-onset asthma? A population-based study in Taiwan.
BMJ Open. 2017 Nov 28;7(11):e018714
Authors: Lin YC, Lai CC, Chien CC, Chen CM, Chiang SR, Ho CH, Weng SF, Cheng KC
OBJECTIVES: To determine whether insomnia at baseline is a risk factor for new-onset asthma.
METHODS: We recruited 48 871 patients with insomnia (insomnia group) newly diagnosed between 2002 and 2007, and 97 742 matched controls without insomnia (control group) from Taiwan's Longitudinal Health Insurance Database 2000. All of the patients were followed up for 4 years to see whether new-onset asthma developed. Patients with previous asthma or insomnia were excluded. The Poisson regression was used to estimate the incidence rate ratios (IRRs) and 95% CIs of asthma. Cox proportional hazard regression was used to calculate the risk of asthma between the two groups.
RESULTS: After a 4-year follow-up, 424 patients in the insomnia group and 409 in the control group developed asthma. The incidence rate of asthma was significantly higher in the insomnia group (22.01vs10.57 per 10 000 person-years). Patients with insomnia have a higher risk of developing new-onset asthma during the 4-year follow-up (HR: 2.08, 95% CI 1.82 to 2.39). The difference remained significant after adjustment (adjusted HR: 1.89, 95% CI 1.64 to 2.17).
CONCLUSIONS: This large population-based study suggests that insomnia at baseline is a risk factor for developing asthma.
PMID: 29187415 [PubMed - indexed for MEDLINE]