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Targeting Cholecystokinin (CCK) and Its Receptor CCKAR in the Airway Smooth Muscle for New Asthma Therapy
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A2744 - Targeting Cholecystokinin (CCK) and Its Receptor CCKAR in the Airway Smooth Muscle for New Asthma Therapy
Author Block: R. M. Panganiban1, M. Sun1, C. Park1, D. I. Kasahara1, B. E. Himes2, E. Israel3, S. T. Weiss4, J. J. Fredberg1, K. G. Tantisira3, S. A. Shore1, Q. Lu1; 1Molecular and Integrative Physiological Sciences, Harvard Chan School of Public Health, Boston, MA, United States, 2Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States, 3Brigham and Womens Hosp, Boston, MA, United States, 4Channing Division of Network Medicine, Brigham and Womens Hosp, Boston, MA, United States.
Rationale: Asthma is an increasingly prevalent pulmonary disease that is characterized by hyperactive contraction of airway smooth muscle (ASM). Obesity, a chronic condition afflicting millions of people worldwide, predisposes individuals to the development of asthma but the underlying mechanisms remain elusive. Using Next-generation deep sequencing followed by qRT-PCR validation, we have found that cholecystokinin, which is best known for inducing smooth muscle contraction in the gut, is expressed and elevated in the lung of obese mice. Here, we examine the expression and function of CCK and CCKAR in the lung and investigate its potential role in obesity-induced airway hyperresponsiveness (AHR).
Methods and Results: Immunohistochemical analysis indicates that CCK expression is mostly localized in ASM. In vitro studies show that treatment of ASM cells with long chain free fatty acids increases CCK expression. Interestingly, we have also found that the CCK receptor, CCK-AR, is highly expressed in ASM. We showed that CCK agonist, A71623, increases the stiffening and contraction of primary human ASM cells as measured by optical magnetic twisting cytometry (OMTC) and traction force microscopy (TFM); such action by the agonist is blocked by the pretreatment of CCKAR antagonists (proglumide, lorglumide and devazepide) and by CRISPR-mediated inactivation of CCKAR. In both high fat diet-induced and db/db obese mice, intranasal administration of CCKAR antagonist, proglumide (50 mg/kg), reduced innate AHR as assessed by forced oscillation technique (flexiVent).
Conclusions: Together, our data reveal a novel role for CCK/CCK-AR in mediating ASM contraction in the lung and suggest a possibility of developing CCK/CCKAR antagonists into new therapeutics for obesity-associated asthma.
Author Block: R. M. Panganiban1, M. Sun1, C. Park1, D. I. Kasahara1, B. E. Himes2, E. Israel3, S. T. Weiss4, J. J. Fredberg1, K. G. Tantisira3, S. A. Shore1, Q. Lu1; 1Molecular and Integrative Physiological Sciences, Harvard Chan School of Public Health, Boston, MA, United States, 2Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States, 3Brigham and Womens Hosp, Boston, MA, United States, 4Channing Division of Network Medicine, Brigham and Womens Hosp, Boston, MA, United States.
Rationale: Asthma is an increasingly prevalent pulmonary disease that is characterized by hyperactive contraction of airway smooth muscle (ASM). Obesity, a chronic condition afflicting millions of people worldwide, predisposes individuals to the development of asthma but the underlying mechanisms remain elusive. Using Next-generation deep sequencing followed by qRT-PCR validation, we have found that cholecystokinin, which is best known for inducing smooth muscle contraction in the gut, is expressed and elevated in the lung of obese mice. Here, we examine the expression and function of CCK and CCKAR in the lung and investigate its potential role in obesity-induced airway hyperresponsiveness (AHR).
Methods and Results: Immunohistochemical analysis indicates that CCK expression is mostly localized in ASM. In vitro studies show that treatment of ASM cells with long chain free fatty acids increases CCK expression. Interestingly, we have also found that the CCK receptor, CCK-AR, is highly expressed in ASM. We showed that CCK agonist, A71623, increases the stiffening and contraction of primary human ASM cells as measured by optical magnetic twisting cytometry (OMTC) and traction force microscopy (TFM); such action by the agonist is blocked by the pretreatment of CCKAR antagonists (proglumide, lorglumide and devazepide) and by CRISPR-mediated inactivation of CCKAR. In both high fat diet-induced and db/db obese mice, intranasal administration of CCKAR antagonist, proglumide (50 mg/kg), reduced innate AHR as assessed by forced oscillation technique (flexiVent).
Conclusions: Together, our data reveal a novel role for CCK/CCK-AR in mediating ASM contraction in the lung and suggest a possibility of developing CCK/CCKAR antagonists into new therapeutics for obesity-associated asthma.
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