Obese Asthmatics are Characterised by Altered Adipose Tissue Macrophage Activation

Abstract

Adipose tissue-derived inflammation is linked to obesity-related co-morbidities. This study aimed to quantify and immuno-phenotype adipose tissue macrophages (ATMs) from obese asthmatics and obese non-asthmatics, and to examine associations between adipose tissue, systemic and airway inflammation.

Visceral (VAT) and sub-cutaneous (SAT) adipose tissue were collected from obese adults undergoing bariatric surgery and processed to obtain the stromovascular fraction. Pro- (M1) and anti-inflammatory (M2) macrophages were quantified by flow cytometry. Cytospins of induced sputum were stained for differential cell counts. Plasma C reactive protein (CRP) and CD163 were measured by ELISA.

VAT contained a higher number of ATMs compared to SAT. A higher percentage of M1 ATMs was observed in VAT of obese asthmatics compared to obese non-asthmatics. The M1:M2 ratio in VAT was negatively associated with FEV₁%. Sputum macrophage count was correlated positively with M1 ATMs and negatively with M2 ATMs in VAT. In obese asthmatics, CRP was positively associated with M1:M2 ratio in VAT. There were no associations with CD163. An elevated ratio of M1:M2 ATMs was observed in VAT of obese asthmatics with increased disease severity.

VAT inflammation with increased pro-inflammatory macrophages (M1) occurs in obese asthma and may be a determinant of systemic inflammation and asthma severity.

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Clinical experience of ingenol mebutate gel for the treatment of Bowen's disease

Abstract

There are only a few anecdotal case reports about Bowen's disease (BD) treated with ingenol mebutate (IM) gel but no clinical study has been published yet. The aim of this study was to evaluate the effectiveness of IM gel in the treatment of BD and to observe the therapeutic efficacy of IM alone or IM with ablative fractional laser pretreatment. Nineteen patients with BD or squamous cell carcinoma in situ confirmed by skin biopsy were enrolled. IM was applied with 0.015% gel on facial lesions for 3 days consecutively and 0.05% gel on other sites for 2 days consecutively, with a 5-mm application margin around the visible lesion. Nine patients applied IM gel immediately following fractional CO₂ laser treatment. Two patients were lost to follow up and a total of 17 patients were enrolled. Nine patients (9/17, 52.9%) had a clinically complete response at 2 months after treatment. Among the patients treated with the fractional CO₂ laser before applying IM gel, eight (8/9, 88.9%) showed a complete response and one (1/9, 11.1%) showed partial response. Among the patients treated with IM gel alone, only one patient (1/8, 12.5%) showed a complete response, four (4/8, 50%) showed a partial response and three (3/8, 37.5%) did not respond to therapy. IM gel alone seems to have limited value for treatment of BD; however, a combination therapy with the ablative fractional laser can increase its therapeutic effectiveness.

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Mild case of Hailey–Hailey disease caused by a novel ATP2C1 mutation

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Detection of human papillomavirus in actinic keratosis

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Neutrophilia, gelatinase release and microvascular leakage induced by human mast cell tryptase in a mouse model: Lack of a role of protease activated receptor 2 (PAR2)

Abstract

Background

Tryptase, the most abundant protease of the human mast cell, has been implicated as a key mediator of allergic inflammation that acts through activation of PAR2.

Objectives

To investigate the contribution of PAR2 in the pro-inflammatory actions mediated by tryptase in a mice model.

Methods

We have injected recombinant human βII-tryptase into the peritoneum of PAR2-deficient and wild-type C57BL/6 mice. After 6, 12 and 24 hours mice were euthanized, peritoneal lavage performed and inflammatory changes investigated.

Results

Tryptase stimulated an increase in neutrophil numbers in the peritoneum, but responses did not differ between PAR2-deficient and wild-type mice. Heat-inactivation of tryptase or pre-incubation with a selective tryptase inhibitor reduced neutrophilia, but neutrophil accumulation was not elicited with a peptide agonist of PAR2 (SLIGRL-NH₂). Zymography indicated that tryptase stimulated the release of matrix metalloproteinases (MMP) 2 and 9 in the peritoneum of both mouse strains. Studies involving immunomagnetic isolation of neutrophils suggested that neutrophils represent the major cellular source of tryptase-induced MMP2 and MMP9. At 24 h after tryptase injection there was increased microvascular leakage as indicated by high levels of albumin in peritoneal lavage fluid, and this appeared to be partially abolished by heat-inactivating tryptase or addition of a protease inhibitor. There was no corresponding increase in levels of histamine or total protein. The extent of tryptase-induced microvascular leakage or gelatinase release into the peritoneum did not differ between PAR2-deficient and wild-type mice.

Conclusions

Our findings indicate that tryptase is a potent stimulus for neutrophil accumulation, MMP release and microvascular leakage. Though these actions required an intact catalytic site, the primary mechanism of tryptase in vivo would appear to involve processes independent of PAR2.

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Repeated vaccination with tetanus toxoid of plasma donors with pre-existing specific IgE transiently elevates tetanus-specific IgE but does not induce allergic symptoms

Abstract

IgE responses against allergens have acquired much attention due to their pathogenic nature as mediators of allergic reactions. In contrast, IgE responses against vaccines like Diphtheria-Tetanus-Pertussis (DTP) and the potential persistence of IgE production have received relatively little attention, presumably because of the low prevalence of allergic symptoms. In general, common early sensitivity reactions against vaccines, including tetanus toxoid, consist of mild local reactions and are not contraindicative of future vaccinations (1, 2).

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Step-down of inhaled corticosteroids in non-eosinophilic asthma: a prospective trial in real life

Abstract

Background

While non-eosinophilic asthmatics are usually considered poorly responsive to inhaled corticosteroids (ICS), studies assessing a step-down of ICS in this specific population are currently lacking.

Objectives

To assess the proportion of non-eosinophilic asthmatics in whom ICS may be withdrawn without any clinical degradation and to determine the predictive markers of a failure to stop treatment with ICS.

Methods

This prospective study was completed by 36 non-eosinophilic asthmatics, defined by sputum eosinophils <3% and blood eosinophils <400/μL. In these patients, whichever the baseline asthma control level, the dose of ICS was gradually reduced every 3 months until they met the failure criteria or successfully discontinued ICS for 6 months. The failure criteria were an ACQ score ≥1.5 with an increase from baseline >0.5 or a number of severe exacerbations during the study which was greater than the number during the year prior to the baseline visit. Receiver-operating characteristic (ROC) curves were constructed to assess predictors of a failure to stop ICS. This study is registered with ClinicalTrials. gov, number NCT02169323.

Results

In 14 patients (39%), ICS were completely withdrawn and in 10 further patients (28%), ICS were stepped-down to a reduced ICS dose without any deterioration of asthma control and exacerbation rate. Baseline predictors of a failure to stop ICS were a greater age (area under ROC curve [ROC AUC] and [95% CI]: 0.77 [0.62-0.93]) and elevated blood eosinophils (ROC AUC [95% CI]: 0.77 [0.61-0.93]). After the first step-down of ICS, the best predictor was an elevated blood eosinophil count (ROC AUC [95% CI]: 0.85 [0.72-0.99]).

Conclusions & Clinical Relevance

Withdrawing or reducing the dose of ICS is feasible in two thirds of non-eosinophilic asthmatics irrespective of baseline asthma control. An elevated blood eosinophil count may predict the failure to stop ICS.

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