Airway hyperresponsiveness induced by repeated esophageal infusion of HCl in guinea pigs.
Gastroesophageal reflux is a common disorder closely related to chronic airway diseases, such as chronic cough, asthma, chronic bronchitis, and chronic obstructive disease. Indeed, gastroesophageal acid reflux into the respiratory tract causes bronchoconstriction, but the underlying mechanisms have still not been clarified. This study aimed to elucidate functional changes of bronchial smooth muscles (BSMs) isolated from guinea pigs in an animal model of gastroesophageal reflux. The marked airway inflammation, hyperresponsiveness and remodeling were observed after guinea pigs were exposed to intraesophageal HCl infusion for 14 days. In addition, contractile responses to acetylcholine (ACh), KCl, electrical field stimulation, and extracellular Ca(2+) were greater in guinea pigs infused with HCl compared with control groups. The L-type voltage-dependent Ca(2+) channels (L-VDCC) blocker, nicardipine, significantly inhibited ACh- and Ca(2+)-enhanced BSM contractions in guinea pigs infused with HCl. The Rho-kinase inhibitor, Y27632, attenuated ACh-enhanced BSM contractions in guinea pigs infused with HCl. Moreover, mRNA and protein expressions for muscarinic M2 and M3 receptors, RhoA, and L-VDCC in BSM were detected by real-time PCR and Western blot. Expressions of mRNA and protein for muscarinic M3 receptors, RhoA, and L-VDCC were greater than in BSM of HCl-infused guinea pigs, whereas levels of muscarinic M2 receptors were unchanged. We demonstrate that acid infusion to the lower esophagus and, subsequently, microaspiration into the respiratory tract in guinea pigs leads to airway hyperresponsiveness and overactive BSM. Functional and molecular results indicate that overactive BSM is the reason for enhancement of extracellular Ca(2+) influx via L-VDCC and Ca(2+) sensitization through Rho-kinase signaling.
1 Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; and.
Yan-Mei
YM
Cheng
Ai-Li
AL
Cao
Jian-Pu
JP
Zheng
Hong-Wei
HW
Wang
Yong-Shun
YS
Sun
Chun-Fang
CF
Liu
Bei-Bei
BB
Zhang
Yi
Y
Wang
Sheng-Liang
SL
Zhu
Da-Zheng
DZ
Wu
D056151:Airway Remodeling / Q000502:physiology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004947:Esophagus / Q000378:metabolism / Q000473:pathology*; D005764:Gastroesophageal Reflux / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D006168:Guinea Pigs; D006851:Hydrochloric Acid / Q000494:pharmacology*; D008297:Male; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D043585:Receptor, Muscarinic M2 / Q000235:genetics / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
D020746:Calcium Channels, L-Type; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D054460:rho-Associated Kinases; D006851:Hydrochloric Acid
L-type voltage-operated Ca2+ channels; Rho-kinase; airway hyperresponsiveness; gastroesophageal reflux; muscarinic receptors