Effects of ex vivo Gamma-Tocopherol on Airway Macrophage Function in Healthy and Mild Allergic Asthmatics

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Abstract

Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate gamma-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from non-smoking healthy (n = 6) and mild house dust mite-sensitive (HDM) allergic asthmatics (n = 6) were treated ex vivo with GT (300 μM) or saline (control). Phagocytosis of opsonized Zymosan A bioparticles (S. cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (P < 0.05) internalization of attached Zymosan bioparticles and decreased (P < 0.05) macrophage expression of CD206, CD36 and CD86 in allergic asthmatics but not in controls. Overall, GT caused down-regulation of both innate and adaptive immune response elements and atopic status appears to be an important factor.

Keywords: 

J Innate Immun. Author manuscript; available in PMC May 8, 2014.

Published in final edited form as:

J Innate Immun. 2013; 5(6): 613–624.

Published online May 8, 2013. doi:  10.1159/000350234

PMCID: PMC3939603

NIHMSID: NIHMS539930

Marianne Geiser, PhD,^a,c,*,1 John C. Lay, DVM, PhD,^a,b William D. Bennett, PhD,^a,c Haibo Zhou, PhD,^a,d Xiaoyan Wang, PhD,^a,d David B. Peden, MD, MPH,^a,b,c and Neil E. Alexis, PhD^a,b

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Abstract

Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate gamma-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from non-smoking healthy (n = 6) and mild house dust mite-sensitive (HDM) allergic asthmatics (n = 6) were treated ex vivo with GT (300 μM) or saline (control). Phagocytosis of opsonized Zymosan A bioparticles (S. cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (P - 0.05) internalization of attached Zymosan bioparticles and decreased (P - 0.05) macrophage expression of CD206, CD36 and CD86 in allergic asthmatics but not in controls. Overall, GT caused down-regulation of both innate and adaptive immune response elements and atopic status appears to be an important factor.

Keywords: allergy, asthma, macrophages, phagocytosis, flow cytometry, gamma-tocopherol, host defense

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Interferon-gamma regulates growth and controls Fcgamma receptor expression and activation in human intestinal mast cells

Research article

Gernot Sellge, Miriam Barkowsky, Sigrid Kramer, Thomas Gebhardt, Leif E Sander, Axel Lorentz and Stephan C Bischoff

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BMC Immunology 2014, 15:27  doi:10.1186/1471-2172-15-27

Published: 5 July 2014

Abstract (provisional)

Background

Development and function of tissue resident mast cells (MCs) is tightly controlled by various cytokines, most of which belong to the typical T helper (Th) 2-type cytokines such as IL-3 and IL-4. The effects of the Th1-type cytokine IFN-gamma on human MCs is less clear.

Results

Here, we analyzed the effects of IFN-gamma on tissue-derived, mature human MCs. We found that INF-gamma decreases proliferation, without affecting apoptosis in human intestinal MCs cultured in the presence of optimal concentrations of stem cell factor (SCF) or SCF and IL-4. However, in the absence of growth factors or at suboptimal concentrations of SCF, INF-gamma promotes survival through inhibition of MC apoptosis. Interestingly, we found that INF-gamma has no effect on FcepsilonRI expression and FcepsilonRI-mediated release of histamine and leukotriene (LT)C4, while it has profound effects on FcgammaR expression and activation. We show that intestinal MCs express FcgammaRI, FcgammaRIIa, and FcgammaRIIc, whereas FcgammaRIIb expression was found in only 40% of the isolates and FcgammaRIII was never detectable. INF-gamma strongly increases FcgammaRI and decreases FcgammaRIIa expression. INF-gamma-naive MCs produce LTC4 but fail to degranulate upon crosslinking of surface-bound monomeric IgG. In contrast, INF-gamma-treated MCs rapidly release granule-stored histamine in addition to de novo-synthesized LTC4.

Conclusion

In summary, we identify INF-gamma as an important regulator of tissue-resident human MCs. IFN-gamma displays a dual function by blocking extensive MC proliferation, while decreasing apoptosis in starving MCs and enhancing FcgammaRI expression and activation. These results emphasize the involvement of mucosal MCs in Th1-mediated disorders.

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Comprehensive multiplexed protein quantitation delineates eosinophilic and neutrophilic experimental asthma

Research article

Maria Bergquist, Sofia Jonasson, Josephine Hjoberg, Göran Hedenstierna and Jörg Hanrieder

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BMC Pulmonary Medicine 2014, 14:110  doi:10.1186/1471-2466-14-110

Published: 4 July 2014

Abstract (provisional)

Background

Improvements in asthma diagnosis and management require deeper understanding of the heterogeneity of the complex airway inflammation. We hypothesise that differences in the two major inflammatory phenotypes of asthma; eosinophilic and neutrophilic asthma, will be reflected in the lung protein expression profile of murine asthma models and can be delineated using proteomics of bronchoalveolar lavage (BAL).

Methods

BAL from mice challenged with ovalbumin (OVA/OVA) alone (standard model of asthma, here considered eosinophilic) or OVA in combination with endotoxin (OVA/LPS, model of neutrophilic asthma) was analysed using liquid chromatography coupled to high resolution mass spectrometry, and compared with steroid-treated animals and healthy controls. In addition, conventional inflammatory markers were analysed using multiplexed ELISA (Bio-PlexTM assay). Multivariate statistics was performed on integrative proteomic fingerprints using principal component analysis. Proteomic data were complemented with lung mechanics and BAL cell counts.

Results

Several of the analysed proteins displayed significant differences between the controls and either or both of the two models reflecting eosinophilic and neutrophilic asthma. Most of the proteins found with mass spectrometry analysis displayed a considerable increase in neutrophilic asthma compared with the other groups. Conversely, the larger number of the inflammatory markers analysed with Bio-PlexTM analysis were found to be increased in the eosinophilic model. In addition, major inflammation markers were correlated to peripheral airway closure, while commonly used asthma biomarkers only reflect central inflammation.

Conclusion

Our data suggest that the commercial markers we are currently relying on to diagnose asthma subtypes are not giving us comprehensive or specific enough information. The analysed protein profiles allowed to discriminate the two models and may add useful information for characterization of different asthma phenotypes.

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The Cohort for Childhood Origin of Asthma and allergic diseases (COCOA) study: design, rationale and methods

Study protocol

Hyeon-Jong Yang, So-Yeon Lee, Dong In Suh, Youn Ho Shin, Byoung-Ju Kim, Ju-Hee Seo,Hyoung Yoon Chang, Kyung Won Kim, Kangmo Ahn, Yee-Jin Shin, Kyung-Sook Lee, Cheol Min Lee, Se-Young Oh, Ho Kim, Jong-Han Leem, Hwan Cheol Kim, Eun-Jin Kim, Joo-Shil Lee and Soo-Jong Hong

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BMC Pulmonary Medicine 2014, 14:109  doi:10.1186/1471-2466-14-109

Published: 3 July 2014

Abstract (provisional)

Background

This paper describes the background, aim, and design of a prospective birth-cohort study in Korea called the COhort for Childhood Origin of Asthma and allergic diseases (COCOA). COCOA objectives are to investigate the individual and interactive effects of genetics, perinatal environment, maternal lifestyle, and psychosocial stress of mother and child on pediatric susceptibility to allergic diseases.

Methods

The participants in COCOA represents a Korean inner-city population. Recruitment started on 19 November, 2007 and will continue until 31 December, 2015. Recruitment is performed at five medical centers and eight public-health centers for antenatal care located in Seoul. Participating mother-baby pairs are followed from before birth to adolescents. COCOA investigates whether the following five environmental variables contribute causally to the development and natural course of allergic diseases: (1) perinatal indoor factors (i.e. house-dust mite, bacterial endotoxin, tobacco smoking, and particulate matters 2.5 and 10), (2) perinatal outdoor pollutants, (3) maternal prenatal psychosocial stress and the child's neurodevelopment, (4) perinatal nutrition, and (5) perinatal microbiome. Cord blood and blood samples from the child are used to assess whether the child's genes and epigenetic changes influence allergic-disease susceptibility. Thus, COCOA aims to investigate the contributions of genetics, epigenetics, and various environmental factors in early life to allergic-disease susceptibility in later life. How these variables interact to shape allergic-disease susceptibility is also a key aim.

The COCOA data collection schedule includes 11 routine standardized follow-up assessments of all children at 6 months and every year until 10 years of age, regardless of allergic-disease development. The mothers will complete multiple questionnaires to assess the baseline characteristics, the child's exposure to environmental factors, maternal pre- and post-natal psychological stress, and the child's neurodevelopment, nutritional status, and development of allergic and respiratory illnesses. The child's microbiome, genes, epigenetics, plasma cytokine levels, and neuropsychological status, the microbiome of the residence, and the levels of indoor and outdoor pollutants are measured by standard procedures.

Discussion

The COCOA study will improve our understanding of how individual genetic or environmental risk factors influence susceptibility to allergic disease and how these variables interact to shape the phenotype of allergic diseases.

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Allergic airway inflammation induces the migration of dendritic cells into airway sensory ganglia

Research

Duc Dung Le, Sabine Rochlitzer, Axel Fischer, Sebastian Heck, Thomas Tschernig, Martina Sester, Robert Bals, Tobias Welte, Armin Braun and Quoc Thai Dinh

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Respiratory Research 2014, 15:73  doi:10.1186/1465-9921-15-73

Published: 30 June 2014

Abstract (provisional)

Background

A neuroimmune crosstalk between dendritic cells (DCs) and airway nerves in the lung has recently been reported. However, the presence of DCs in airway sensory ganglia under normal and allergic conditions has not been explored so far. Therefore, this study aims to investigate the localisation, distribution and proliferation of DCs in airway sensory ganglia under allergic airway inflammation.

Methods

Using the house dust mite (HDM) model for allergic airway inflammation BALB/c mice were exposed to HDM extract intranasally (25 mug/50 mul) for 5 consecutive days a week over 7 weeks. Vagal jugular-nodose ganglia complex (JNC) sections were immunofluorescence analysed for DC-markers (MHC II, CD11c, CD103), the neuronal marker PGP 9.5 and the neuropeptide calcitonin gene-related peptide (CGRP) and glutamine synthetase (GS) as a marker for satellite glia cells (SGCs). To address the original source of DCs in sensory ganglia, proliferation study was also carried in this study.

Results

Immune cells with characteristic DC-phenotype were found to be closely located to SGCs and vagal sensory neurons under physiological conditions. The percentage of DCs in relation to neurons was significantly increased by allergic airway inflammation in comparison to the controls (HDM 51.38 +/- 2.38% vs. control 28.16 +/- 2.86%, p < 0.001). The present study also demonstrated that DCs were shown to proliferate in jugular-nodose ganglia, however, the proliferation rate of DCs is not significantly changed in the two treated animal groups (proliferating DCs/ total DCs: HDM 0.89 +/- 0.38%, vs. control 1.19 +/- 0.54%, p = 0.68). Also, increased number of CGRP-positive neurons was found in JNC after allergic sensitisation and challenge (HDM 31.16 +/- 5.41% vs. control 7.16 +/- 1.53%, p < 0.001).

Conclusion

The present findings suggest that DCs may migrate from outside into the ganglia to interact with sensory neurons enhancing or protecting the allergic airway inflammation. The increase of DCs as well as CGRP-positive neurons in airway ganglia by allergic airway inflammation indicate that intraganglionic DCs and neurons expressing CGRP may contribute to the pathogenesis of bronchial asthma. To understand this neuroimmune interaction in allergic airway inflammation further functional experiments should be carried out in future studies.

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Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

BMJ. 2014 Apr 9;348:g2545. doi: 10.1136/bmj.g2545.

Jefferson T1, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ.

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Abstract

OBJECTIVE:

To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments ("regulatory information").

DESIGN:

Systematic review of regulatory information.

DATA SOURCES:

Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES:

Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza.

MAIN OUTCOME MEASURES:

Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population.

RESULTS:

From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P-0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval -0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for "pneumonia," and no clinical study reports reported laboratory or diagnostic confirmation of "pneumonia." The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on asymptomatic influenza and no evidence of a reduction in transmission. In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined "on-treatment" and "off-treatment" periods (risk difference 1.06%, 0.07% to 2.76%; NNTH 94, 36 to 1538) and there was a dose-response effect on psychiatric events in two "pivotal" treatment trials of oseltamivir, at 75 mg (standard dose) and 150 mg (high dose) twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the risk of headaches on-treatment (risk difference 3.15%, 0.88% to 5.78%; NNTH 32, 18 to 115), renal events with treatment (0.67%, -0.01% to 2.93%), and nausea while receiving treatment (4.15%, 0.86% to 9.51%; NNTH 25, 11 to 116).

CONCLUSIONS:

In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.

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Revista da Associação Médica Brasileira

Volume 59, Issue 6, November–December 2013, Pages 594–599

Open Access

Original article

Prevalence of obesity in asthma and its relations with asthma severity and control ^☆

Prevalência de obesidade na asma e suas relações com gravidade e controle da asma ^☆

• Gabriele Carra Forte^a, 
• Denis Maltz Grutcki^a, 
• Samuel Millán Menegotto^a, 
• Rosemary Petrik Pereira^a, 
• Paulo de Tarso Roth Dalcin^a, b, , 

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DOI: 10.1016/j.ramb.2013.06.015

Open Access funded by Brazilian Medical Association

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Abstract

Objective

To determine the prevalence of obesity in asthmatic patients attending at an outpatient clinic, and to investigate its relationships with asthma severity and level of asthma control.

Methods

In a cross-sectional study we recruited patients aged 11 years and older with confirmed asthma diagnosis from the outpatient asthma clinic of Hospital de Clínicas de Porto Alegre, Brazil. They underwent an evaluation by a general questionnaire, an asthma control questionnaire and by pulmonary function tests. Nutritional status was classified by body mass index (BMI).

Results

272 patients were included in the study. Mean age was 51.1 ± 16.5 years and there were 206 (74.9%) female patients. Mean BMI was 27.5 ± 5.3 kg/m², and 96 (35.3%) patients were classified as normal weight, 97 (35.7%) as overweight and 79 (29%) as obesity. There was a significant higher proportion of female than male patients (34.3% vs. 13.2%, p = 0.002) in the obesity group. There were no significant differences with respect to asthma control (p = 0.741) and severity classification (p = 0.506). The FEV₁% predicted was significantly higher in the obese than in the non-obese group (73.7% vs. 67.2%, p = 0.037). Logistic regression analysis identified sex (OR = 3.84, p = 0.002) as an independent factor associated with obesity.

Conclusions

This study showed a high prevalence of obesity in asthmatic patients. Obese and non-obese subjects were similar in regard to asthma severity and level of asthma control. Female sex was associated with obesity in this asthma population.

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