Involucrasin B suppresses airway inflammation in obese asthma by inhibiting the TLR4-NF-κB-NLRP3 pathway.

BACKGROUND: Obese asthma is an asthma phenotype that causes more severe lung inflammation and airway hyperresponsiveness than allergic asthma and it is resistant to conventional therapy. Involucrasin B (IB) is a dihydroflavonoid isolated from Shuteria involucrata (Wall.) Wight & Arn., a traditional "Dai" and "Wa" medicine was used in southern China to treat the "phlegm and wetness of sputum" (obesity disease) as well as lung inflammation. However, whether IB can ameliorate obese asthma remains unclear, and the underlying mechanisms and molecular expression in obese asthma specifically targeted by IB are still not fully understood. METHODS: An in vivo C57BL/6 J mouse model of obese asthma was established using house dust mites (HDMs) and high-fat diet (HFD) as inducers to evaluate the therapeutic effect of IB. An in vitro cell culture of human THP-1 monocytic cell culture was used to investigate the effect of IB after the treatment with lipopolysaccharide (LPS) and palmitic acid (PA). RESULTS: In vivo, we found that intervention with IB improved airway hyperresponsiveness and lung histopathology and significantly inhibited the secretion of relevant inflammatory factors, such as interleukin (IL)-1ß, IL-17A, and IL-22 in bronchoalveolar lavage fluid, and total-IgE and HDM-IgE in serum compared with the model group (HFD+HDM). The findings indicate that IB could decrease the expression of granulocyte receptor 1 (Gr-1) and neutrophil extracellular traps (NETs) in lung tissue, as well as the expression of NLR family pyrin domain containing 3 (NLRP3) and inducible nitric oxide synthase in M1 macrophages (M1). IB also reduced the population of ILC3/Th17 cells, which are responsible for producing IL-17A, a crucial mediator of neutrophil-mediated inflammation, confirming that the therapeutic effect of IB in obesity-related asthma was related to neutrophils and M1 cells. In addition, IB regulated lipid metabolism and inhibited the production of macrophages in adipose tissue. The in vitro results revealed that IB inhibited the secretion of IL-1ß, IL-18, and tumor necrosis factor-α (TNF-α) from THP-1 cells, and the expression of NLRP3-related protein in THP-1 cells compared with the model groups (LPS, PA, and LPS+PA), confirming that the action of IB involved the TLR4-NF-κB-NLRP3 pathway. CONCLUSION: This study demonstrated the therapeutic effect of IB in obese asthma for the first time and further clarified its mechanistic pathway as the TLR4-NF-κB-NLRP3 pathway.

Predictive Roles of Basal Metabolic Rate and Muscle Mass in Lung Function among Patients with Obese Asthma: A Prospective Cohort Study.

BACKGROUND: The metabolic-status-related mechanisms underlying the deterioration of the lung function in obese asthma have not been completely elucidated. OBJECTIVE: This study aimed to investigate the basal metabolic rate (BMR) in patients with obese asthma, its association with the lung function, and its mediating role in the impact of obesity on the lung function. METHODS: A 12-month prospective cohort study (n = 598) was conducted in a real-world setting, comparing clinical, body composition, BMR, and lung function data between patients with obese (n = 282) and non-obese (n = 316) asthma. Path model mediation analyses for the BMR and skeletal muscle mass (SMM) were conducted. We also explored the effects of the BMR on the long-term lung function in patients with asthma. RESULTS: Patients with obese asthma exhibited greater airway obstruction, with lower FEV1 (1.99 vs. 2.29 L), FVC (3.02 vs. 3.33 L), and FEV1/FVC (65.5 vs. 68.2%) values compared to patients with non-obese asthma. The patients with obese asthma also had higher BMRs (1284.27 vs. 1210.08 kcal/d) and SMM (23.53 vs. 22.10 kg). Both the BMR and SMM mediated the relationship between obesity and the lung function spirometers (FEV1, %FEV1, FVC, %FVC, and FEV1/FVC). A higher BMR or SMM was associated with better long-term lung function. CONCLUSIONS: Our study highlights the significance of the BMR and SMM in mediating the relationship between obesity and spirometry in patients with asthma, and in determining the long-term lung function. Interventions for obese asthma should focus not only on reducing adiposity but also on maintaining a high BMR.

TRP channels associated with macrophages as targets for the treatment of obese asthma.

Globally, obesity and asthma pose significant health challenges, with obesity being a key factor influencing asthma. Despite this, effective treatments for obese asthma, a distinct phenotype, remain elusive. Since the discovery of transient receptor potential (TRP) channels in 1969, their value as therapeutic targets for various diseases has been acknowledged. TRP channels, present in adipose tissue cells, influence fat cell heat production and the secretion of adipokines and cytokines, which are closely associated with asthma and obesity. This paper aims to investigate the mechanisms by which obesity exacerbates asthma-related inflammation and suggests that targeting TRP channels in adipose tissue could potentially suppress obese asthma and offer novel insights into its treatment.

Obese Asthma Phenotype Is Associated with hsa-miR-26a-1-3p and hsa-miR-376a-3p Modulating the IGF Axis.

Clarifying inflammatory processes and categorising asthma into phenotypes and endotypes improves asthma management. Obesity worsens severe asthma and reduces quality of life, although its specific molecular impact remains unclear. We previously demonstrated that hsa-miR-26a-1-3p and hsa-miR-376a-3p, biomarkers related to an inflammatory profile, discriminate eosinophilic from non-eosinophilic asthmatics. We aimed to study hsa-miR-26a-1-3p, hsa-miR-376a-3p, and their target genes in asthmatic subjects with or without obesity to find biomarkers and comprehend obese asthma mechanisms. Lung tissue samples were obtained from asthmatic patients (n = 16) and healthy subjects (n = 20). We measured miRNA expression using RT-qPCR and protein levels (IGF axis) by ELISA in confirmation samples from eosinophilic (n = 38) and non-eosinophilic (n = 39) obese (n = 26) and non-obese (n = 51) asthma patients. Asthmatic lungs showed higher hsa-miR-26a-1-3p and hsa-miR-376a-3p expression than healthy lungs. A study of seven genes regulated by these miRNAs revealed differential expression of IGFBP3 between asthma patients and healthy individuals. In obese asthma patients, we found higher hsa-miR-26a-1-3p and IGF-1R values and lower values for hsa-miR-376a-3p and IGFBP-3. Hsa-miR-26a-1-3p and IGFBP-3 were directly and inversely correlated with body mass index, respectively. Hsa-miR-26a-1-3p and hsa-miR-376a-3p could be used as biomarkers to phenotype patients with eosinophilic and non-eosinophilic asthma in relation to comorbid obesity.

1-O-alkyl-glycerols from Squid Berryteuthis magister Reduce Inflammation and Modify Fatty Acid and Plasmalogen Metabolism in Asthma Associated with Obesity.

Asthma associated with obesity is considered the most severe phenotype and can be challenging to manage with standard medications. Marine-derived 1-O-alkyl-glycerols (AGs), as precursors for plasmalogen synthesis, have high biological activity, making them a promising substance for pharmacology. This study aimed to investigate the effect of AGs from squid Berryteuthis magister on lung function, fatty acid and plasmalogen levels, and cytokine and adipokine production in obese patients with asthma. The investigational trial included 19 patients with mild asthma associated with obesity who received 0.4 g of AGs daily for three months in addition to their standard treatment. The effects of AGs were evaluated at one and three months of treatment. The results of the study demonstrated that intake of AGs increased the FEV1 and FEV1/VC ratios, and significantly decreased the ACQ score in 17 of the 19 patients after three months of treatment. The intake of AGs increased concentration of plasmalogen and n-3 PUFA in plasma, and modified leptin/adiponectin production by adipose tissue. The supplementation of AGs decreased the plasma levels of inflammatory cytokines (TNF-α, IL-4, and IL-17a), and oxylipins (TXB2 and LTB4), suggesting an anti-inflammatory property of AGs. In conclusion, 1-O-alkyl-glycerols could be a promising dietary supplement for improving pulmonary function and reducing inflammation in obese asthma patients, and a natural source for plasmalogen synthesis. The study highlighted that the beneficial effects of AG consumption can be observed after one month of treatment, with gradual improvement after three months of supplementation.

Growth differentiation factor 15 protects the airway by inhibiting cell pyroptosis in obese asthmatic mice through the phosphoinositide 3-kinase/AKT pathway.

Obese asthma is a form of refractory asthma with inflammation as the underlying mechanism. The specific mechanism of action of anti-inflammatory growth differentiation factor 15 (GDF15) in obese asthma is unclear. The purpose of this study was to explore the effect of GDF15 on cell pyroptosis in obese asthma and to determine its mechanism of airway protection. Male C57BL6/J mice were fed with a high-fat diet, sensitized, and challenged with ovalbumin. Recombinant human (rh)GDF15 was administered 1 h before the challenge. GDF15 treatment significantly reduced airway inflammatory cell infiltration, mucus hypersecretion and airway resistant, and decreased cell counts and inflammatory factors in bronchoalveolar lavage fluid. Serum inflammatory factors decreased, and the increased levels of NLR family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and gasdermin-D (GSDMD-N) in obese asthmatic mice were inhibited. Furthermore, the suppressed phosphoinositide 3-kinase (PI3K)/AKT signal pathway was activated after rhGDF15 treatment. The same result was obtained by overexpression of GDF15 in human bronchial epithelial cells induced by lipopolysaccharide (LPS) in vitro, and the effect of GDF15 was reversed after the application of a PI3K pathway inhibitor. Thus, GDF15 could protect the airway by inhibiting cell pyroptosis in obese asthmatic mice through the PI3K/AKT signaling pathway.

Apigenin ameliorates non-eosinophilic inflammation, dysregulated immune homeostasis and mitochondria-mediated airway epithelial cell apoptosis in chronic obese asthma via the ROS-ASK1-MAPK pathway.

BACKGROUND: Obese asthma is one of the important asthma phenotypes that have received wide attention in recent years. Excessive oxidative stress and different inflammatory endotypes may be important reasons for the complex symptoms, frequent aggravation, and resistance to traditional treatments of obese asthma. Apigenin (API), is a flavonoid natural small molecule compound with good anti-inflammatory and antioxidant activity in various diseases and proved to have the potential efficacy to combat obese asthma. METHODS: In vivo, this study fed C57BL/6 J mice with high-fat diets(HFD)for 12 weeks and then stimulated them with OVA for 6 weeks to establish a model of chronic obese asthma, while different doses of oral API or dexamethasone were used for therapeutic interventions. In vitro, this study used HDM to stimulate human bronchial cells (HBEs) to establish the model and intervened with API or Selonsertib (SEL). RESULTS: This study clarified that OVAinduced a type of mixed granulocytic asthma with elevated neutrophils and eosinophils in obese male mice fed with long-term HFD, which also exhibited mixed TH17/TH1/TH2 inflammation. Apigenin effectively suppressed this complex inflammation and acted as a regulator of immune homeostasis. Meanwhile, apigenin reduced AHR, inflammatory cell infiltration, airway epithelial cell apoptosis, airway collagen deposition, and lung oxidative stress via the ROS-ASK1-MAPK pathway in an obese asthma mouse model. In vitro, this study found that apigenin altered the binding status of TRAF6 to ASK1, inhibited ASK1 phosphorylation, and protected against ubiquitin-dependent degradation of ASK1, suggesting that ROS-activated ASK1 may be an important target for apigenin to exert anti-inflammatory and anti-apoptotic effects. To further verify the intervention mechanism, this study clarified that apigenin improved cell viability and mitochondrial function and inhibited apoptosis by interfering with the ROS-ASK1-MAPK pathway. CONCLUSIONS: This study demonstrates for the first time the therapeutic effect of apigenin in chronic obese asthma and further clarifies its potential therapeutic targets. In addition, this study clarifies the specificity of chronic obese asthma and provides new options for its treatment.

Overview of asthma patients followed up in a tertiary clinic.

Summary: Background. Asthma is a disease that combines different biological mechanisms, inflammatory pathways, and phenotypic features. Our aim was to investigate the demographic and disease characteristics of patients with asthma and to reveal the distribution with different phenotypes according to endotype groups. Methods. Patients were identified as eosinophilic if the absolute eosinophil count was measured at least once ≥ 300/µL during the oral corticosteroid free period or ≥ 150/µL under oral corticosteroids. Patients sensitive to at least one inhalant allergen with skin prick test and/ or spIgE measurement were defined as allergic. They were categorized into four main endotypes. Results. Data of 405 asthma patients with a median age of 50.9 years were analyzed. The prominent clinical and phenotypic characteristics of the study group were being obese (43.2%) or overweight (32%), severe asthma (49.6%), adult-onset (56.1%) or late-onset asthma (35.3%). The distribution of the four main endotypes according to eosinophilic and/or allergic status, is as follows: 22.7% allergic-eosinophilic (AE), 27.9% nonallergic-eosinophilic (NAE), 22.9% allergic-noneosinophilic (ANE), 26.4% nonallergic-noneosinophilic (NANE). While most severe asthma patients were in the AE and NAE groups, those with early-onset asthma were in AE and ANE, and those with late-onset asthma were in the NAE and NANE groups. The proportion of uncontrolled patients was higher in the NAE group. Among the severe asthma patients, the rate of uncontrolled disease was higher in those with NANE asthma. Conclusions. Different phenotypes were more closely related to some endotypes. This may allow the clinicians to identify patients and predict appropriate treatment modalities and response for individualized care.

Investigational approaches for unmet need in severe asthma.

INTRODUCTION: Molecular antibodies (mAb) targeting inflammatory mediators are effective in T2-high asthma. The recent approval of Tezepelumab presents a novel mAb therapeutic option for those with T2-low asthma. AREAS COVERED: We discuss a number of clinical problems pertinent to severe asthma that are less responsive to current therapies, such as persistent airflow obstruction and airway hyperresponsiveness. We discuss selected investigational approaches, including a number of candidate therapies under investigation in two adaptive platform trials currently in progress, with particular reference to this unmet need, as well as their potential in phenotypes such as neutrophilic asthma and obese asthma, which may or may not overlap with a T2-high phenotype. EXPERT OPINION: The application of discrete targeting approaches to T2-low molecular phenotypes, including those phenotypes in which inflammation may not arise within the airway, has yielded variable results to date. Endotypes associated with T2-low asthma are likely to be diverse but await validation. Investigational therapeutic approaches must, likewise, be diverse if the goal of remission is to become attainable for all those living with asthma.

Positive expiratory pressure: a potential therapy to mitigate acute bronchoconstriction in the asthma of obesity.

Late-onset nonallergic (LONA) asthma in obesity is characterized by increased peripheral airway closure secondary to abnormally collapsible airways. We hypothesized that positive expiratory pressure (PEP) would mitigate the tendency to airway closure during bronchoconstriction, potentially serving as rescue therapy for LONA asthma of obesity. The PC20 [provocative concentration of methacholine causing 20% drop in forced expiratory volume in 1 s (FEV1)] dose of methacholine was determined in 18 obese participants with LONA asthma. At each of four subsequent visits, we used oscillometry to measure input respiratory impedance (Zrs) over 8 min; participants received their PC20 concentration of methacholine aerosol during the first 4.5 min. PEP combinations of either 0 or 10 cmH2O either during and/or after the methacholine delivery were applied, randomized between visits. Parameters characterizing respiratory system mechanics were extracted from the Zrs spectra. In 18 patients with LONA asthma [14 females, body mass index (BMI): 39.6 ± 3.4 kg/m2], 10 cmH2O PEP during methacholine reduced elevations in the central airway resistance, peripheral airway resistance, and elastance, and breathing frequency was also reduced. During the 3.5 min following methacholine delivery, PEP of 10 cmH2O reduced Ax and peripheral elastance compared with no PEP. PEP mitigates the onset of airway narrowing brought on by methacholine challenge and airway closure once it is established. PEP thus might serve as a nonpharmacological therapy to manage acute airway narrowing for obese LONA asthma.NEW & NOTEWORTHY Standard pharmacological treatments are not effective in people with obesity and asthma. We assessed the efficacy of positive expiratory pressure (PEP) as a therapy to mitigate airway hyperresponsiveness in the asthma of obesity. Our results indicate that PEP might serve as a nonpharmacological therapy to manage acute airway narrowing in obese individuals with late-onset nonallergic asthma.

Linggan Wuwei Jiangxin formula ameliorates airway hyperresponsiveness through suppression of IL-1ß and IL-17A expression in allergic asthmatic mice especially with diet-induced obesity.

BACKGROUND: Obese asthma represents a disease phenotype, which is associated with worse disease control and unresponsiveness to standard anti-inflammatory regimens, including inhaled corticosteroids. Obesity-related innate airway hyperresponsiveness (AHR) plays a role in this asthma phenotype via activation of the IL-1ß/innate lymphoid cell 3 (ILC3)/IL-17A pathway. Linggan Wuwei Jiangxin (LGWWJX) formula may be a promising therapeutic option for obese asthma according to traditional Chinese medicine theory, clinical experience and related research. METHODS: The murine model of allergic asthma with obesity was induced by ovalbumin (OVA) sensitization and challenge in combination with a high fat diet (HFD). LGWWJX formula intervention was oral administrated. AHR and bronchoalveolar lavage fluid (BALF) cellularity were measured. Lung and liver histopathology assessment was performed by haematoxylin and eosin (H&E) staining. IL-1ß and IL-17A in BALF and serum were evaluated by ELISA. Additionally, the influence of different concentrations of LGWWJX formula on IL-1ß stimulated IL-17A mRNA expression in ILC3 cells was evaluated in vitro. RESULTS: LGWWJX treatment significantly reduced AHR and allergic airway inflammatory responses in asthmatic mice, as measured by pulmonary histopathology and BALF cellularity, and these effects were more pronounced in obese asthmatic mice. While eosinophil infiltration in BALF was suppressed with LGWWJX treatment in non-obese asthmatic mice, neutrophils and basophils were significantly decreased in obese asthmatic mice. Notably, LGWWJX also demonstrated remarkable efficacy for weight loss and improvements in hepatic steatosis in mice fed with a HFD. Furthermore, the protein levels of IL-1ß in both serum and BALF, as well as those of BALF IL-17A, declined with LGWWJX intervention in both obese and non-obese asthmatic mice, and results from ex-vivo experiments found that LGWWJX significantly attenuated the expression of IL-17A in ILC3 cells with or without stimulation by IL-1ß. CONCLUSIONS: LGWWJX may exert a protective effect on asthmatic individuals, especially those with concurrent obesity, most likely through mechanisms including the inhibition of the IL-1ß/ILC3/IL-17A/AHR axis, anti-inflammatory effects, weight loss, and the regulation of lipid metabolism. This suggests a promising role of LGWWJX, alone or in combination with anti-inflammatory agents, for the treatment of obese asthma.

Glucagon-like peptide-1 receptor agonist inhibits aeroallergen-induced activation of ILC2 and neutrophilic airway inflammation in obese mice.

BACKGROUND: Obesity is a risk factor for the development of asthma. However, pharmacologic therapeutic strategies that specifically target obese asthmatics have not been identified. We hypothesize that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment inhibits aeroallergen-induced early innate airway inflammation in a mouse model of asthma in the setting of obesity. METHODS: SWR (lean) and TALLYHO (obese) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or PBS for 4 consecutive days concurrent with GLP-1RA or vehicle treatment. RESULTS: TALLYHO mice had greater Alt-Ext-induced airway neutrophilia and lung protein expression of IL-5, IL-13, CCL11, CXCL1, and CXCL5, in addition to ICAM-1 expression on lung epithelial cells compared with SWR mice, and all endpoints were reduced by GLP-1RA treatment. Alt-Ext significantly increased BALF IL-33 in both TALLYHO and SWR mice compared to PBS challenge, but there was no difference in the BALF IL-33 levels between these two strains. However, TALLYHO, but not SWR, mice had significantly higher airway TSLP in BALF following Alt-Ext challenge compared to PBS, and BALF TSLP was significantly greater in TALLYHO mice compared to SWR mice following airway Alt-Ext challenge. GLP-1RA treatment significantly decreased the Alt-Ext-induced TSLP and IL-33 release in TALLYHO mice. While TSLP or ST2 inhibition with a neutralizing antibody decreased airway eosinophils, they did not reduce airway neutrophils in TALLYHO mice. CONCLUSIONS: These results suggest that GLP-1RA treatment may be a novel pharmacologic therapeutic strategy for obese persons with asthma by inhibiting aeroallergen-induced neutrophilia, a feature not seen with either TSLP or ST2 inhibition.

Obese-Asthma Phenotype Self-Management: A Literature Review.

PROBLEM: Recent identification of the early-onset obese-asthma phenotype has spurred exploration of ways to promote effective, long-term management behaviors for children with this comorbid presentation. Few studies have examined the needs of children with both asthma and obesity and little is known about optimal management options for this unique population. Therefore, the authors aimed to review, critique, and synthesize existing published research on health-management programs designed for children with comorbid asthma and obesity in order to describe the state of the science and recommend next steps in creating pediatric management programs. ELIGIBILITY CRITERIA: Articles selected for a full-text review were pediatric-focused, included children with both asthma and obesity diagnoses, and discussed the implementation and evaluation of a management program or the evaluation of a management behavior. SAMPLE: Fifteen articles were selected for review based on the inclusion criteria. RESULTS: Studies that included current evidence-based elements had better results than those that did not include such elements. CONCLUSIONS: Based on this review, it is recommended that researchers use theory based, multicomponent, multimodal, family-focused, behaviorally-based interventions that address systems-level influences, social determinates of health, and children's developmental needs over time. Additionally, there is a need for studies with sample sizes adequate for power analyses that include the youngest children with asthma and obesity. IMPLICATIONS: The need for effective programs for pediatric obese-asthma phenotype management creates the opportunity for nursing-led research and interventions to foster long-term health promotion for affected children and families.

Regulatory effect of mitoQ on the mtROS-NLRP3 inflammasome pathway in leptin-pretreated BEAS-2 cells.

Obese asthma is a phenotype of asthma whose occurrence is gradually increasing in both adults and children. The majority of studies have demonstrated that obesity is a major risk factor for asthma and the effect of obesity on the lungs is considerable. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been previously demonstrated to serve a role in obese asthma mediated by mitochondrial reactive oxygen species (mtROS). The aim of the present in vitro study was to investigate the effect of leptin on airway epithelial cells and the protective effect of the mitochondrial-targeted antioxidant mitoquinone (mitoQ). Human normal bronchial epithelial cell lines BEAS-2 cells were used and divided into 6 groups: Control group (negative control), DMSO group (solvent control), lipopolysaccharide (LPS) group (positive control), LPS + mitoQ group, Leptin group and Leptin + mitoQ group. CCK8 assay was used to establish the optimal concentration and incubation time of the drugs. mitoTracker probe and mitoSOX reagent were used to detect the integrity of mitochondrial membranes and the content of mtROS. mRNA expression levels were detected by reverse transcription-quantitative PCR analysis. It was revealed that the mitochondrial membrane was disrupted in the Leptin group, which recovered after treatment with mitoQ. As a result, the production of mitochondrial reactive oxygen species (mtROS) in the Leptin group was significantly increased (P<0.01), but following treatment with mitoQ, this overproduction of mtROS was significantly decreased to normal levels (P<0.01). Furthermore, the expression levels of NOD-, LRR- and pyrin domain-containing protein 3 NLRP3 and caspase-1 mRNA in the leptin-pretreated BEAS-2 cells were significantly increased compared with those in the control group (P<0.01), while they were decreased following mitoQ treatment (P<0.01). Taken together, these data suggested that leptin may promote airway inflammation partially through upregulating the mtROS-NLRP3 inflammasome signaling pathway in airway epithelial cells and mitoQ may be a potential treatment for obese asthma.

Central airway collapse is related to obesity independent of asthma phenotype.

BACKGROUND AND OBJECTIVE: Late-onset non-allergic asthma in obesity is characterized by an abnormally compliant, collapsible lung periphery; it is not known whether this abnormality exists in proximal airways. We sought to compare collapsibility of central airways between lean and obese individuals with and without asthma. METHODS: A cross-sectional study comparing luminal area and shape (circularity) of the trachea, left mainstem bronchus, right bronchus intermedius and right inferior lobar bronchus at RV and TLC by CT was conducted. RESULTS: In 11 lean controls (BMI: 22.4 (21.5, 23.8) kg/m2 ), 10 lean individuals with asthma (23.6 (22.0, 24.8) kg/m2 ), 10 obese controls (45.5 (40.3, 48.5) kg/m2 ) and 21 obese individuals with asthma (39.2 (35.8, 42.9) kg/m2 ), lumen area and circularity increased significantly with an increase in lung volume from RV to TLC for all four airways (P < 0.05 for all). Changes in area and circularity with lung volume were similar in obese individuals with and without asthma, and both obese groups had severe airway collapse at RV. In multivariate analysis, change in lumen area was related to BMI and change in circularity to waist circumference, but neither was related to asthma diagnosis. CONCLUSION: Excessive collapse of the central airways is related to obesity, and occurs in both obese controls and obese asthma. Increased airway collapse could contribute to ventilation abnormalities in obese individuals particularly at lower lung volumes, and complicate asthma in obese individuals.

Metformin alleviates allergic airway inflammation and increases Treg cells in obese asthma.

Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.

How to apply the personalized medicine in obesity-associated asthma?

INTRODUCTION: Obesity-associated asthma (OA) is frequently severe, with an increased rate of hospitalizations, numerous comorbidities and low response to corticosteroids. Despite progress in applying for personalized medicine in asthma, no specific recommendations exist for the management of OA. AREAS COVERED: The aim of this review is to summarize recent data about the relationship obesity-asthma, describe clinical characteristics, potential mechanisms involved and possible therapeutic interventions to improve OA outcomes. Extensive research in the PubMed was performed using the following terms: "asthma and obesity" and "obese asthma" in combination with "phenotypes", "airway inflammation", "biomarkers", "lung function", "weight loss", "lifestyle interventions", "therapies" Currently two phenotypes are described. Early-onset atopic asthma is conventional allergic asthma aggravated by the pro-inflammatory properties of adipose tissue in excess, while late-onset non-atopic asthma is due to airway dysfunction as a consequence of the chronic lung compression caused by the obese chest walls. Previous data showed that different therapeutic strategies used in weight loss have a positive impact on OA outcomes. EXPERT OPINION: The presence of a multidisciplinary team (chest physician, nutritionist, exercise physiologist, physiotherapist, psychologist, bariatric surgeon) and the collaboration between different specialists are mandatory to optimize the management and to apply the personalized medicine in OA.

Weight Loss for Children and Adults with Obesity and Asthma. A Systematic Review of Randomized Controlled Trials.

Background: Asthma and obesity are major public health problems, affecting hundreds of millions of people worldwide. Obesity is associated with increased asthma risk and severity, and lower asthma-related quality of life. Objective: In this systematic review, we aimed to evaluate whether weight loss in subjects with obesity and asthma leads to improvement in asthma-related outcomes. Data Sources and Extraction: We searched PubMed and Google Scholar for all studies in English published January 2000-December 2018. Studies were included if they were randomized, controlled clinical trials (RCTs) for overweight/obese children or adults with asthma, with sufficient data to assess outcomes and study quality. Non-randomized and non-controlled studies were excluded, as well as those in subjects without overweight/obesity, or with non-asthmatic controls. Synthesis: We identified four RCTs involving children (total n = 246) and six involving adults (n = 502). All interventions were designed for weight loss and varied from dietary restrictions to multifactorial interventions with exercise training and cognitive behavioral therapy; the duration of intervention ranged from 8 weeks to 18 months. All RCTs reported successful improvements in weight or body mass index (-0.14 standard deviation scores to -15.9% BMI reduction in children, 1.8%-14.5% weight loss in adults). RCTs generally reported improvements in asthma-related quality of life and, to some degree, asthma control. RCTs involving adults also reported improvements in lung function (FEV1, FVC, TLC), while RCTs in children showed less consistent results. Conclusions: These findings suggest that weight loss in subjects with obesity and asthma may improve asthma outcomes. However, there was wide variability in populations studied, baseline and post-intervention assessments, follow-up length, outcome definition and reporting, and statistical approaches, which hindered the ability to compare studies, perform a pooled analysis, or assess generalizability. Primary Source of Funding: U.S. National Institutes of Health (NIH).

Dietary Fatty Acids Amplify Inflammatory Responses to Infection through p38 MAPK Signaling.

Obesity is an important risk factor for severe asthma exacerbations, which are mainly caused by respiratory infections. Dietary fatty acids, which are increased systemically in obese patients and are further increased after high-fat meals, affect the innate immune system and may contribute to dysfunctional immune responses to respiratory infection. In this study we investigated the effects of dietary fatty acids on immune responses to respiratory infection in pulmonary fibroblasts and a bronchial epithelial cell line (BEAS-2B). Cells were challenged with BSA-conjugated fatty acids (ω-6 polyunsaturated fatty acids [PUFAs], ω-3 PUFAs, or saturated fatty acids [SFAs]) +/- the viral mimic polyinosinic:polycytidylic acid (poly[I:C]) or bacterial compound lipoteichoic acid (LTA), and release of proinflammatory cytokines was measured. In both cell types, challenge with arachidonic acid (AA) (ω-6 PUFA) and poly(I:C) or LTA led to substantially greater IL-6 and CXCL8 release than either challenge alone, demonstrating synergy. In epithelial cells, palmitic acid (SFA) combined with poly(I:C) also led to greater IL-6 release. The underlying signaling pathways of AA and poly(I:C)- or LTA-induced cytokine release were examined using specific signaling inhibitors and IB. Cytokine production in pulmonary fibroblasts was prostaglandin dependent, and synergistic upregulation occurred via p38 mitogen-activated protein kinase signaling, whereas cytokine production in bronchial epithelial cell lines was mainly mediated through JNK and p38 mitogen-activated protein kinase signaling. We confirmed these findings using rhinovirus infection, demonstrating that AA enhances rhinovirus-induced cytokine release. This study suggests that during respiratory infection, increased levels of dietary ω-6 PUFAs and SFAs may lead to more severe airway inflammation and may contribute to and/or increase the severity of asthma exacerbations.