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

Ronald Allan M. Panganiban, Zhiping Yang, Maoyun Sun, Chan Young Park, David I. Kasahara, Niccole Schaible, Ramaswamy Krishnan, Alvin T. Kho, Elliot Israel, Marc B. Hershenson, Scott T. Weiss, Blanca E. Himes, Jeffrey J. Fredberg, Kelan G. Tantisira, Stephanie A. Shore and Quan Lu ()
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Ronald Allan M. Panganiban: Harvard T.H. Chan School of Public Health
Zhiping Yang: Harvard T.H. Chan School of Public Health
Maoyun Sun: Harvard T.H. Chan School of Public Health
Chan Young Park: Harvard T.H. Chan School of Public Health
David I. Kasahara: Harvard T.H. Chan School of Public Health
Niccole Schaible: Beth Israel Deaconess Medical Center
Ramaswamy Krishnan: Beth Israel Deaconess Medical Center
Alvin T. Kho: Boston Children’s Hospital
Elliot Israel: Brigham and Women’s Hospital, Harvard Medical School
Marc B. Hershenson: University of Michigan Medical School
Scott T. Weiss: Brigham and Women’s Hospital, Harvard Medical School
Blanca E. Himes: University of Pennsylvania
Jeffrey J. Fredberg: Harvard T.H. Chan School of Public Health
Kelan G. Tantisira: University of California San Diego and Rady Children’s Hospital
Stephanie A. Shore: Harvard T.H. Chan School of Public Health
Quan Lu: Harvard T.H. Chan School of Public Health

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-022-35739-8

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