Role of the Adiponectin Binding Protein, T-Cadherin (Cdh13), in Allergic Airways Responses in Mice

Williams, Alison S.; Kasahara, David I.; Verbout, Norah G.; Fedulov, Alexey V.; Zhu, Min; Si, Huiqing; Wurmbrand, Allison P.; Hug, Christopher; Ranscht, Barbara; Shore, Stephanie A.

doi:10.1371/journal.pone.0041088

Cited by 39 publications

(43 citation statements)

References 60 publications

(95 reference statements)

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“…For example, adiponectin, an antiinflammatory mediator that is decreased in obesity, functions in lean mice to inhibit allergic airway inflammation and airway reactivity (45,46), an activity that appears to be related to its serum levels (47). Conversely, leptin, an adipokine that is elevated in obesity, can increase airway reactivity and serum IgE in an allergic mouse model (48).…”

Section: Pre-existing Asthma Complicated By Obesitymentioning

confidence: 99%

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

Dixon

Poynter

2016

Am J Respir Cell Mol Biol

125

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The majority of patients with severe or difficult-to-control asthma in the United States are obese. Epidemiological studies have clearly established that obese patients tend to have worse asthma control and increased hospitalizations and do not respond to standard controller therapy as well as lean patients with asthma. Less clear are the mechanistic underpinnings for the striking clinical differences between lean and obese patients with asthma. Because obesity is principally a disorder of metabolism and energy regulation, processes fundamental to the function of every cell and system within the body, it is not surprising that it affects the respiratory system; it is perhaps surprising that it has taken so long to appreciate how dysfunctional metabolism and energy regulation lead to severe airway disease. Although early investigations focused on identifying a common factor in obesity that could promote airway disease, an appreciation has emerged that the asthma of obesity is a manifestation of multiple anomalies related to obesity affecting all the different pathways that cause asthma, and likely also to de novo airway dysfunction. Consequently, all the phenotypes of asthma currently recognized in lean patients (which are profoundly modified by obesity), as well as those unique to one's obesity endotype, likely contribute to obese asthma in a particular individual. This perspective reviews what we have learned from clinical studies and animal models about the phenotypes of asthma in obesity, which show how specific aspects of obesity and altered metabolism might lead to de novo airway disease and profoundly modify existing airway disease.

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Section: Pre-existing Asthma Complicated By Obesitymentioning

confidence: 99%

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

Dixon

Poynter

2016

Am J Respir Cell Mol Biol

125

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“…Male mice (C57BL/6) were purchased from Jackson laboratory (Bar Harbor, ME). Sensitization and challenge to ovalbumin (OVA) were performed as previously described (31). BAL fluid was collected 24 hours after the last OVA inhalation, as previously described (31).…”

Section: Allergen-sensitized and -Challenged Micementioning

confidence: 99%

IL-13 Augments Compressive Stress–Induced Tissue Factor Expression in Human Airway Epithelial Cells

Mitchel¹,

Antoniak

Kim

et al. 2016

Am J Respir Cell Mol Biol

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Tissue factor (TF) is best known as a cellular initiator of coagulation, but it is also a multifunctional protein that has been implicated in multiple pathophysiologic conditions, including asthma. In the lung, airway epithelial cells express TF, but it is unknown how TF expression is regulated by asthma-associated mediators. We investigated the role of IL-13, a type 2 cytokine, alone and in combination with compressive stress, which mimics asthmatic bronchoconstriction, on TF expression and release of TF-positive extracellular vesicles from primary normal human bronchial epithelial cells. Well-differentiated normal human bronchial epithelial cells were treated with IL-13 and compressive stress, alone and in combination. TF mRNA, protein and activity were measured in the cells and conditioned media. TF was also measured in the bronchoalveolar lavage (BAL) fluid of allergen-challenged mice and patients with asthma. IL-13 and compressive stress increased TF expression, but only compressive stress induced TF-positive extracellular vesicle release. Pretreatment with IL-13 augmented compressive stress-induced TF expression and release. TF protein and activity in BAL fluid were increased in allergen-sensitized and -challenged mice. TF was elevated in the BAL fluid of patients with mild asthma after an allergen challenge. Our in vitro and in vivo data indicate close cooperation between mechanical and inflammatory stimuli on TF expression and release of TF-positive extracellular vesicles in the lungs, which may contribute to pathophysiology of asthma.Keywords: asthma; bronchoconstriction; mechanotransduction; coagulation; airway epithelium Clinical RelevanceTwo critical components of asthma-IL-13 and bronchoconstriction-cooperatively work to induce tissue factor (TF) expression and release of TF-positive extracellular vesicles from well-differentiated human bronchial epithelial cells. Furthermore, in both mice and humans, allergen challenge increases the release of TF into bronchoalveolar lavage fluid.Asthma is characterized by chronic airway inflammation and airway hyperresponsiveness (1, 2). Although the immune system is certainly implicated in asthma, a growing body of evidence suggests that airway epithelial cells also initiate and perpetuate disease (3, 4). During asthma exacerbations, airway smooth muscle contracts excessively and the airway becomes narrowed, resulting in buckling of the airway epithelium (5, 6). Epithelial cells in such buckled airways are subjected to a compressive mechanical stress of approximately 30 cm H 2 O (7). Using an in vitro system mimicking the Correspondence and requests for reprints should be addressed to Jin

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“…There is no evidence for differences in anxiety phenotypes, which might otherwise interact with CPP testing (37). Constitutive knockout mice fail to display sizable alterations in locomotion or strength likely to confound CPP testing (38,39). that include ventral midbrain substantia nigra and ventral tegmental area neurons, likely dopaminergic, whose activities are modulated by virtually every abused substance and by most ADHD pharmacotherapeutics (29)(30)(31).…”

Section: Morris Water Mazementioning

confidence: 99%

Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

Drgonová

Walther

Hartstein

et al. 2016

Mol Med

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The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.

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Role of the Adiponectin Binding Protein, T-Cadherin (Cdh13), in Allergic Airways Responses in Mice

Cited by 39 publications

References 60 publications

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

IL-13 Augments Compressive Stress–Induced Tissue Factor Expression in Human Airway Epithelial Cells

Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

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