Metabolic Syndrome and Asthma

Garmendia, Jenny V.; Moreno, Dolores; García, Alexis; Sanctis, Juan B. De

doi:10.2174/1872214807666140107151023

Cited by 27 publications

(22 citation statements)

References 113 publications

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“…FGF21, a novel hormone partnering with insulin in regulation of glucose homeostasis, also signals through FGFR1 and FGFR2 . In support of our findings, previous studies have reported insulin resistance in children and adults with asthma, and an association of asthma with prediabetes and metabolic syndrome . Moreover, our validation experiments inducing loss of differentiation in epithelial cells by depriving them of insulin (which is long established as a necessary component in commercial culture of primary epithelium) demonstrate remarkable potential for insulin deficiency to induce epithelial genes and phenotypes consistent with those observed in asthma, including upregulation of “Th2‐high” markers and loss of competent barrier state.…”

Section: Discussionsupporting

confidence: 88%

Beyond epithelial‐to‐mesenchymal transition: Common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate, and severe asthma

Loffredo

Abdala-Valencia

Anekalla

et al. 2017

Allergy

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Background Epithelial barrier dysfunction is a central feature in the pathogenesis of allergic disease. Epithelial-to-mesenchymal transition (EMT) has been proposed as one mechanism afflicting barrier in asthma. However, genes and pathways involved in aberrant epithelial-mesenchymal signaling, and their relationship to asthma severity, are poorly understood. Methods We used unbiased gene network analysis to evaluate functional convergence in epithelial gene expression signatures across multiple public access transcriptomics datasets of human asthma, followed by text mining to evaluate functional marker relevance of discovered genes. We objectively confirmed these findings in epithelial brushings and primary asthmatic epithelial cells cultured in different biological contexts. Results We found a striking suppression of epithelial differentiation in asthma, overrepresented by insufficiency in insulin and Notch signaling, but with the absence of conventional EMT markers. We identified EFNB2, FGFR1, FGFR2, INSR, IRS2, NOTCH2, TLE1, and NTRK2 as novel markers central to dysregulation of epithelial-mesenchymal signaling, but surprisingly overlooked in asthma research. We found that this “core” signature of asthma is shared by mild, moderate, and severe forms of disease, progressing with severity. Loss of epithelial differentiation induced by insulin deprivation in normal human bronchial epithelial cells cultured in organotypic conditions closely approximated gene expression in asthmatic epithelial brushings. Conclusions The comparative analysis of publically available transcriptomes demonstrated that epithelial barrier dysfunction in asthma is characterized by persistent underlying de-differentiation program with complex etiology. The lasting alteration of the asthmatic epithelial cell transcriptome implicates regulation involving metabolism and epigenetics, beyond EMT driven by injury and repair in chronic inflammation.

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Section: Discussionsupporting

confidence: 88%

Beyond epithelial‐to‐mesenchymal transition: Common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate, and severe asthma

Loffredo

Abdala-Valencia

Anekalla

et al. 2017

Allergy

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“…Several studies report insulin resistance in children and adults with asthma 93, 94 , as well as association of asthma and atopic eczema with pre-diabetes and metabolic syndrome 95 . We found profound changes in serum hormonal profiles of pre-pubertal non-obese allergic children compared to non-allergic controls, as well as chronic rhinosinusitis patients compared to healthy controls, including decreased levels in serum insulin and increased output of thyroid and growth hormones 96 .…”

Section: Mechanisms Of Barrier Defectsmentioning

confidence: 99%

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Schleimer

Berdnikovs

2017

Journal of Allergy and Clinical Immunology

135

122

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Epithelial barriers of the skin, gastrointestinal tract and airway serve common critical functions such as maintaining a physical barrier against environmental insults and allergens, as well as providing a tissue interface balancing the communication between the internal and external environments. We now understand that in allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed towards loss of differentiation, reduced junctional integrity and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre-date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in the initiation of allergic disease, many important questions remain to be answered regarding the mechanisms disrupting the normal barrier function. Although our external environment (proteases, allergens, injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction, using both systems biology tools and causality-driven laboratory experimentation, will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergy.

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“…14 Indeed, it has been shown that the markers of metabolic syndrome such as hypertension, hyperlipidemia, and insulin resistance can be associated with obesity and asthma. 15 Several human studies have reported that increased insulin level and insulin resistance were related to reduced lung function and increased AHR through several mechanisms such as airway smooth muscle proliferation and epithelial damage. 16 In this regard, metabolic syndrome has been shown to worsen asthma control and may have an impact on the treatment process in patients with asthma, 17 especially women.…”

Section: Introductionmentioning

confidence: 99%

Effect of High-fat Diet on Tracheal Responsiveness to Methacholine and Insulin Resistance Index in Ovalbumin-sensitized Male and Female Rats

Ghobadi

Alipour

Keyhanmanesh

et al. 2019

IJAAI

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Epidemiological and clinical studies have demonstrated a close association between obesity and asthma. The current study investigated the effect of high-fat diet on tracheal responsiveness to methacholine and insulin resistance in ovalbumin (OVA) sensitized male and female rats. The rats were divided into eight groups (n=6 per group): female with the normal diet (F+ND), male with the normal diet (M+ND), female OVA-sensitized with the normal diet (F+SND), male OVA-sensitized with the normal diet (M+SND), female with high-fat diet (F+HFD), male with high-fat diet (M+HFD), female OVA-sensitized with high-fat diet (F+SHFD), and male OVA-sensitized with high-fat diet (M+SHFD). All rats were fed for 8 weeks with high-fat diet or standard pelts, and for another 4 weeks, they were sensitized with OVA or saline. At the end of the study, the tracheal responsiveness to methacholine, serum insulin, and blood glucose levels was measured. Also, insulin resistance indexes were determined. OVA-sensitization and diet-induced obesity caused the curve of methacholine concentration response to shifting to the left. In addition, results indicated that the EC50 (the effective concentration of methacholine generating 50% of peak response) in F+SHFD rats was statistically lower than M+SHFD group (p<0.05). Moreover, insulin resistance was higher in the F+SHFD than the M+SHFD group (p<0.001). These results suggest that insulin resistance and metabolic syndrome may be involved in the pathogenesis of obesity associated with OVA-sensitized rats condition, especially in female animals.

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Metabolic Syndrome and Asthma

Cited by 27 publications

References 113 publications

Beyond epithelial‐to‐mesenchymal transition: Common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate, and severe asthma

Beyond epithelial‐to‐mesenchymal transition: Common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate, and severe asthma

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Effect of High-fat Diet on Tracheal Responsiveness to Methacholine and Insulin Resistance Index in Ovalbumin-sensitized Male and Female Rats

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