| Autor: |
Jeffrey J. Fredberg, Blanca E. Himes, Ronald Pangniban, Alvin Koh, Maoyun Sun, Elliot Israel, Quan Lu, David I. Kasahara, Marc Hershenson, Stephanie A. Shore, Scott T. Weiss, Kelan G. Tantisira, Chan Young Park |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.21203/rs.3.rs-841619/v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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