Debugging Obesity-related Airway Hyperresponsiveness by Modulating the Microbiome.
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ABSTRACT:
SUBMITTER: Poynter ME
PROVIDER: S-EPMC6890407 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Obesity is a risk factor for asthma, especially nonallergic asthma. Ozone, a common air pollutant, is a nonallergic asthma trigger. Importantly, ozone-induced decrements in lung function are greater in obese and overweight human subjects than in lean individuals. Obese mice also exhibit exaggerated pulmonary responses to ozone. Ozone causes greater increases in pulmonary resistance, in bronchoalveolar lavage neutrophils, and in airway hyperresponsiveness in obese than in lean mice. Our data indicate that IL-33 plays a role in mediating these events. Ozone causes greater release of IL-33 into bronchoalveolar lavage fluid in obese than in lean mice. Furthermore, an antibody blocking the IL-33 receptor, ST2, attenuates ozone-induced airway hyperresponsiveness in obese but not in lean mice. Our data also indicate a complex role for tumor necrosis factor (TNF)-? in obesity-related effects on the response to ozone. In obese mice, genetic deficiency in either TNF-? or TNF-? receptor 2 augments ozone-induced airway hyperresponsiveness, whereas TNF-? receptor 2 deficiency virtually abolishes ozone-induced airway hyperresponsiveness in lean mice. Finally, obesity is known to alter the gut microbiome. In female mice, antibiotics attenuate obesity-related increases in the effect of ozone on airway hyperresponsiveness, possibly by altering microbial production of short-chain fatty acids. Asthma control is often difficult to achieve in obese patients with asthma. Our data suggest that therapeutics directed against IL-33 may ultimately prove effective in these patients. The data also suggest that dietary manipulations and other strategies (prebiotics, probiotics) that alter the microbiome and/or its metabolic products may represent a new frontier for treating asthma in obese individuals.
| S-EPMC5711270 | biostudies-literature
Project description:Obesity is a known risk factor for allergic asthma. It has been recognized as a key player in the pathogenesis of several inflammatory disorders via activation of macrophages, which is also vital to the development of allergic asthma. We investigated the mechanism of obesity-related asthma and whether treating obesity through exercise or diet ameliorates the severity of asthma in the obesity-related asthma model. We generated diet-induced obesity (DIO) in C57BL/6 mice by high-fat-feeding and ovalbumin-induced asthma (lean-OVA or DIO-OVA). The DIO-OVA mice were then treated with tumor necrosis factor (TNF)-? neutralizing antibody as a TNF-? blockade or a Cl2MDP-containing liposome to induce an alveolar macrophage deficiency. To treat obesity, the DIO-OVA mice were under dietary restrictions or exercised. The pathophysiological and immunological responses were analyzed. Airway hyperresponsiveness (AHR), serum IgE and TNF-? levels in the lung tissue increased in the DIO-OVA mice compared to the lean-OVA mice. Both the TNF-? blockade and depletion of alveolar macrophages in the DIO-OVA mice decreased AHR compared to the DIO-OVA mice. Treating obesity by exercise or through dietary means also reduced pulmonary TNF-? levels and AHR in the DIO-OVA mice. These results suggest that restoring normal body weight is an appropriate strategy for reducing TNF-? levels, and controlling inflammation may help improve asthma severity and control in obesity-related asthma.
| S-EPMC4344461 | biostudies-literature
Project description:This project investigates the mechanisms that underlie asthma-related phenotypes associated with allergen exposure. See http://www.hopkins-genomics.org/asthma/asthma006/index.html The goal of the experiment was to identify genes that change their levels of expression as a consequence of challenge with allergen. The experiments utilized a murine model of human asthma that employed BALB/CJ mice. In this particular sensitization-challenge protocol, the response produced by BALB/CJ mice is representative of a majority of the mouse strains tested. The antigen complex used to sensitize and challenge the mice was ragweed pollen an allergen that is highly relevant to human disease. Keywords: time series, allergen
2005-08-24 | GSE3184 | GEO
Project description:The purpose of this project is to gain a better understanding of the early cytokine-mediated mechanisms that lead to asthma. Keywords: time series, IL13
2005-08-24 | GSE3183 | GEO
Project description:BackgroundAsthma in obese subjects is poorly understood, and these patients are often refractory to standard therapy.ObjectivesWe sought to gain insights into the pathogenesis and treatment of asthma in obese subjects by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness (AHR), and markers of asthmatic inflammation.MethodsWe performed a prospective study of (1) asthmatic and nonasthmatic patients undergoing bariatric surgery compared at baseline and (2) asthmatic patients followed for 12 months after bariatric surgery.ResultsWe studied 23 asthmatic and 21 nonasthmatic patients undergoing bariatric surgery. At baseline, asthmatic patients had lower FEV(1) and forced vital capacity and lower numbers of lymphocytes in bronchoalveolar lavage fluid. After surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score, 1.55 to 0.74; P < .0001) and asthma quality of life (4.87 to 5.87, P < .0001). Airways responsiveness to methacholine improved significantly (methacholine PC(20), 3.9 to 7.28, P = .03). There was a statistically significant interaction between IgE status and change in airways responsiveness (P for interaction = .01). The proportion of lymphocytes in bronchoalveolar lavage fluid and the production of cytokines from activated peripheral blood CD4(+) T cells increased significantly.ConclusionsBariatric surgery improves AHR in obese asthmatic patients with normal serum IgE levels. Weight loss has dichotomous effects on airway physiology and T-cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach.
| S-EPMC3164923 | biostudies-literature
Project description:Airway hyperresponsiveness (AHR) is a clinical feature of asthma and is often in proportion to the underlying severity of the disease. To understand AHR and the mechanisms that contribute to these processes, it is helpful to divide the airway components that affect this feature of asthma into "persistent" and "variable" categories. The persistent component of AHR represents structural changes in the airway, whereas the variable feature relates to inflammatory events. Insight into how these interrelated components of AHR can contribute to asthma is gained by studying treatment effects and models of asthma provocation.
| S-EPMC2914527 | biostudies-other
Project description:Rhinovirus (RV) exposure has been implicated in childhood development of wheeze evoking asthma and exacerbations of underlying airways disease. Studies such as the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) and Childhood Origins of ASThma (COAST) have identified RV as a pathogen inducing severe respiratory disease. RVs also modulate airway hyperresponsiveness (AHR), a key characteristic of such diseases. Although potential factors underlying mechanisms by which RV induces AHR have been postulated, the precise mechanisms of AHR following RV exposure remain elusive.A challenge to RV-related research stems from inadequate models for study. While human models raise ethical concerns and are relatively difficult in terms of subject recruitment, murine models are limited by susceptibility of infection to the relatively uncommon minor group (RV-B) serotypes, strains that are generally associated with infrequent clinical respiratory virus infections. Although a transgenic mouse strain that has been developed has enhanced susceptibility for infection with the common major group (RV-A) serotypes, few studies have focused on RV in the context of allergic airways disease rather than understanding RV-induced AHR. Recently, the receptor for the virulent RV-C CDHR3, was identified, but a dearth of studies have examined RV-C-induced effects in humans.Currently, the mechanisms by which RV infections modulate airway smooth muscle (ASM) shortening or excitation-contraction coupling remain elusive. Further, only one study has investigated the effects of RV on bronchodilatory mechanisms, with only speculation as to mechanisms underlying RV-mediated modulation of bronchoconstriction.
| S-EPMC6206673 | biostudies-literature
Project description:Patients with severe, treatment-refractory asthma are at risk for death from acute exacerbations. The cytokine IL17A has been associated with airway inflammation in severe asthma, and novel therapeutic targets within this pathway are urgently needed. We recently showed that IL17A increases airway contractility by activating the procontractile GTPase RhoA. Here, we explore the therapeutic potential of targeting the RhoA pathway activated by IL17A by inhibiting RhoA guanine nucleotide exchange factors (RhoGEFs), intracellular activators of RhoA. We first used a ribosomal pulldown approach to profile mouse airway smooth muscle by qPCR and identified Arhgef12 as highly expressed among a panel of RhoGEFs. ARHGEF12 was also the most highly expressed RhoGEF in patients with asthma, as found by RNA sequencing. Tracheal rings from Arhgef12-KO mice and WT rings treated with a RhoGEF inhibitor had evidence of decreased contractility and RhoA activation in response to IL17A treatment. In a house dust mite model of allergic sensitization, Arhgef12-KO mice had decreased airway hyperresponsiveness without effects on airway inflammation. Taken together, our results show that Arhgef12 is necessary for IL17A-induced airway contractility and identify a therapeutic target for severe asthma.
| S-EPMC6238747 | biostudies-literature
Project description:RationaleAllergically inflamed mice exhibit airway hyperresponsiveness to inhaled methacholine, which computer simulations of lung impedance suggest is due to enhanced lung derecruitment and which we sought to verify in the present study.MethodsBALB/c mice were sensitized and challenged with ovalbumin to induce allergic inflammation; the control mice were sensitized but received no challenge. The mice were then challenged with inhaled methacholine and respiratory system impedance tracked for the following 10 minutes. Respiratory elastance (H) was estimated from each impedance measurement. One group of mice was ventilated with 100% O(2) during this procedure and another group was ventilated with air. After the procedure, the mice were killed and ventilated with pure N(2), after which the trachea was tied off and the lungs were imaged with micro-computed tomography (micro-CT).ResultsH was significantly higher in allergic mice than in control animals after methacholine challenge. The ratio of H at the end of the measurement period between allergic and nonallergic mice ventilated with O(2) was 1.36, indicating substantial derecruitment in the allergic animals. The ratio between lung volumes determined by micro-CT in the control and the allergic mice was also 1.36, indicative of a corresponding volume loss due to absorption atelectasis. Micro-CT images and histograms of Hounsfield units from the lungs also showed increased volume loss in the allergic mice compared with control animals after methacholine challenge.ConclusionsThese results support the conclusion that airway closure is a major component of hyperresponsiveness in allergically inflamed mice.
| S-EPMC1899295 | biostudies-literature
Project description:RationaleAsthma is characterized by increases in airway resistance, pulmonary remodeling, and lung inflammation. The cytokine transforming growth factor (TGF)-beta has been shown to have a central role in asthma pathogenesis and in mouse models of allergic airway disease.ObjectivesTo determine the contribution of TGF-beta to airway hyperresponsiveness (AHR), we examined the time course, source, and isoform specificity of TGF-beta production in an in vivo mouse asthma model. To then elucidate the function of TGF-beta in AHR, inflammation, and pulmonary fibrosis, we examined the effects of blocking TGF-beta signaling with neutralizing antibody.MethodsMice were sensitized and challenged with ovalbumin (OVA) to establish allergic airway disease. TGF-beta activity was neutralized by intranasal administration of monoclonal antibody.Measurements and main resultsTGF-beta1 protein levels were increased in OVA-challenged lungs versus naive controls, and airway epithelial cells were shown to be a likely source of TGF-beta1. In addition, TGF-beta1 levels were elevated in OVA-exposed IL-5-null mice, which fail to recruit eosinophils into the airways. Neutralization of TGF-beta1 with specific antibody had no significant effect on airway inflammation and eosinophilia, although anti-TGF-beta1 antibody enhanced OVA-induced AHR and suppressed pulmonary fibrosis.ConclusionsThese data show that TGF-beta1 is the main TGF-beta isoform produced after OVA challenge, with a likely cellular source being the airway epithelium. The effects of blocking TGF-beta1 signaling had differential effects on AHR, fibrosis, and inflammation. While TGF-beta neutralization may be beneficial to abrogating airway remodeling, it may be detrimental to lung function by increasing AHR.
| S-EPMC2078678 | biostudies-literature