An Overview of the Obese-Asthma Phenotype in Children

Asthma is the most common chronic disease in childhood. Overweight and obesity are included among the comorbidities considered in patients with difficult-to-treat asthma, suggesting a specific phenotype of the disease. Therefore, the constant increase in obesity prevalence in children and adolescents raises concerns about the parallel increase of obesity-associated asthma. The possible correlation between obesity and asthma has been investigated over the last decade by different authors, who suggest a complex multifactorial relationship. Although the particular non-eosinophilic endotype of obesity-related asthma supports the concept that high body weight precedes asthma development, there is ongoing debate about the direct causality of these two entities. A number of mechanisms may be involved in asthma in combination with obesity disease in children, including reduced physical activity, abnormal ventilation, chronic systemic inflammation, hormonal influences, genetics and additional comorbidities, such as gastroesophageal reflux and dysfunctional breathing. The identification of the obesity-related asthma phenotype is crucial to initiate specific therapeutic management. Besides the cornerstones of asthma treatment, lifestyle should be optimized, with interventions aiming to promote physical exercise, healthy diet, and comorbidities. Future studies should clarify the exact association between asthma and obesity and the mechanisms underlying the pathogenesis of these two related conditions with the aim to define personalized therapeutic strategies for asthma management in this population.

The Role of CD4+ T Cells and Microbiota in the Pathogenesis of Asthma

Asthma, a chronic respiratory disease involving variable airflow limitations, exhibits two phenotypes: eosinophilic and neutrophilic. The asthma phenotype must be considered because the prognosis and drug responsiveness of eosinophilic and neutrophilic asthma differ. CD4+ T cells are the main determinant of asthma phenotype. Th2, Th9 and Tfh cells mediate the development of eosinophilic asthma, whereas Th1 and Th17 cells mediate the development of neutrophilic asthma. Elucidating the biological roles of CD4+ T cells is thus essential for developing effective asthma treatments and predicting a patient’s prognosis. Commensal bacteria also play a key role in the pathogenesis of asthma. Beneficial bacteria within the host act to suppress asthma, whereas harmful bacteria exacerbate asthma. Recent literature indicates that imbalances between beneficial and harmful bacteria affect the differentiation of CD4+ T cells, leading to the development of asthma. Correcting bacterial imbalances using probiotics reportedly improves asthma symptoms. In this review, we investigate the effects of crosstalk between the microbiota and CD4+ T cells on the development of asthma.

OGR1-dependent regulation of the allergen-induced asthma phenotype

The proton-sensing receptor, ovarian cancer G protein-coupled receptor (OGR1) has been shown to be expressed in airway smooth muscle (ASM) cells and capable of promoting ASM contraction in response to decreased extracellular pH. OGR1 knockout mice (OGR1KO) are reported to be resistant to asthma features induced by inhaled allergen. We recently described certain benzodiazepines as OGR1 activators capable of mediating both pro-contractile and pro-relaxant signaling in ASM cells. Here we assess the effect of treatment with the benzodiazepines lorazepam or sulazepam on the asthma phenotype, in wild type (WT) and OGR1KO mice subjected to inhaled house dust mite (HDM; Dermatophagoides pteronyssius) challenge for three weeks. In contrast to previously published reports, both WT and OGR1KO mice developed significant allergen-induced lung inflammation and airway hyperresponsiveness (AHR). In WT mice, treatment with sulazepam (a Gs-biased OGR1 agonist), but not lorazepam (a balanced OGR1 agonist), prevented allergen-induced AHR, although neither drug inhibited lung inflammation. The protection from development of AHR conferred by sulazepam was absent in OGR1KO mice. Treatment of WT mice with sulazepam also resulted in significant inhibition of HDM-induced collagen accumulation in the lung tissue. These findings suggest OGR1 expression is not a requirement for development of the allergen-induced asthma phenotype, but OGR1 can be targeted by the Gs-biased OGR1 agonist sulazepam (but not the balanced agonist lorazepam) to protect from allergen-induced AHR, possibly mediated via suppression of chronic bronchoconstriction and airway remodeling in the absence of effects on airway inflammation.

Differential Regulation of Interferon Signaling Pathways in CD4+ T Cells of the Low Type-2 Obesity-Associated Asthma Phenotype

In the era of personalized medicine, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as asthma phenotypes including obesity-associated asthma, are urgently needed. Peripheral blood was drawn from 10 obese, non-atopic asthmatic adults with a high body mass index (BMI; 36.67 ± 6.90); 10 non-obese, non-atopic asthmatic adults with normal BMI (23.88 ± 2.73); and 10 healthy controls with normal BMI (23.62 ± 3.74). All asthmatic patients were considered to represent a low type-2 asthma phenotype according to selective clinical parameters. RNA sequencing (RNA-Seq) was conducted on peripheral blood CD4+ T cells. Thousands of differentially expressed genes were identified in both asthma groups compared with heathy controls. The expression of interferon (IFN)-stimulated genes associated with IFN-related signaling pathways was specifically affected in obese asthmatics, while the gap junction and G protein-coupled receptor (GPCR) ligand binding pathways were enriched in both asthma groups. Furthermore, obesity gene markers were also upregulated in CD4+ T cells from obese asthmatics compared with the two other groups. Additionally, the enriched genes of the three abovementioned pathways showed a unique correlation pattern with various laboratory and clinical parameters. The specific activation of IFN-related signaling and viral infection pathways might provide a novel view of the molecular mechanisms associated with the development of the low type-2 obesity-associated asthma phenotype, which is a step ahead in the development of new stratified therapeutic approaches.