Gallbladder, Sphincter of Oddi, Cholecystokinin, and Opioid Inter-Relationship

Krishnamurthy, Gerbail T.; Krishnamurthy, Shakuntala

doi:10.1007/978-3-662-22654-4_6

Cited by 2 publications

(1 citation statement)

References 45 publications

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“…Interestingly, the other CCK receptor CCKBR is not expressed at all in the ASM cells (no reads in the RNAseq data). The expression and function of CCKAR have been mostly investigated in extrapulmonary tissues such as the gallbladder and the sphincter of Oddi where it mediates CCK-induced contraction and relaxation, respectively 48,49 . However, CCKAR's surprising high expression in ASM cells suggests a potential biological role for the receptor in the ASM and airways.…”

Section: Resultsmentioning

confidence: 99%

Antagonizing the metabolic hormone cholecystokinin (CCK) and its receptor CCKAR in the lung abolishes obesity-induced airway hyperresponsiveness

Pangniban

Sun

Park

et al. 2021

Preprint

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Obesity is a significant co-morbidity that associates with increased prevalence and severity of asthma. The mechanism underlying the obesity-asthma association remains poorly understood, and for obese asthmatics there is no effective therapy for obese asthmatics. Here we show that cholecystokinin (CCK)—a metabolic hormone best known for its roles in satiety regulation and fat metabolism–is increased in the lungs of obese mice and that pharmacological blockade of CCK and its receptor (CCKAR) signaling in the lung abolishes obesity-associated airway hyperresponsiveness (AHR)—a hallmark of asthma. By mining existing RNA-seq transcriptomic data, we first discovered CCKAR as a highly expressed G-protein-coupled receptor in primary human airway smooth muscle (ASM) cells. Interestingly, CCK is also expressed in ASM cells and is induced by free fatty acids. Activation of CCKAR by CCK induces ASM stiffening and contraction, which is abolished by either CRISPR-mediated CCKAR inactivation or CCKAR antagonists. In vivo, CCK levels are elevated in the lung of both genetically obese (db/db) and diet-induced obese mice. Importantly, intranasal administration of highly potent CCKAR antagonists (proglumide and devazepide) abolishes AHR in both genetically obese and diet-induced obese mice. Together, our results reveal an unexpected role for the metabolic hormone CCK and its receptor CCKAR in airway smooth muscle cells and in obesity-associated asthma. Our study provides critical pre-clinical data that support the repurposing of CCKAR antagonists as a novel therapy for obese asthmatics.

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Section: Resultsmentioning

confidence: 99%

Antagonizing the metabolic hormone cholecystokinin (CCK) and its receptor CCKAR in the lung abolishes obesity-induced airway hyperresponsiveness

Pangniban

Sun

Park

et al. 2021

Preprint

View full text Add to dashboard Cite

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Antagonizing cholecystokinin A receptor in the lung attenuates obesity-induced airway hyperresponsiveness

et al. 2023

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Obesity increases asthma prevalence and severity. However, the underlying mechanisms are poorly understood, and consequently, therapeutic options for asthma patients with obesity remain limited. Here we report that cholecystokinin—a metabolic hormone best known for its role in signaling satiation and fat metabolism—is increased in the lungs of obese mice and that pharmacological blockade of cholecystokinin A receptor signaling reduces obesity-associated airway hyperresponsiveness. Activation of cholecystokinin A receptor by the hormone induces contraction of airway smooth muscle cells. In vivo, cholecystokinin level is elevated in the lungs of both genetically and diet-induced obese mice. Importantly, intranasal administration of cholecystokinin A receptor antagonists (proglumide and devazepide) suppresses the airway hyperresponsiveness in the obese mice. Together, our results reveal an unexpected role for cholecystokinin in the lung and support the repurposing of cholecystokinin A receptor antagonists as a potential therapy for asthma patients with obesity.

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Gallbladder, Sphincter of Oddi, Cholecystokinin, and Opioid Inter-Relationship

Cited by 2 publications

References 45 publications

Antagonizing the metabolic hormone cholecystokinin (CCK) and its receptor CCKAR in the lung abolishes obesity-induced airway hyperresponsiveness

Antagonizing the metabolic hormone cholecystokinin (CCK) and its receptor CCKAR in the lung abolishes obesity-induced airway hyperresponsiveness

Antagonizing cholecystokinin A receptor in the lung attenuates obesity-induced airway hyperresponsiveness

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