Tongjiang Hewei Decoction Improves Airway Hyperresponsiveness in Gastroesophageal Reflux Cough by Inhibiting ADAM33 and Epac1/Rap1 Pathway

ABSTRACT Gastroesophageal reflux disease is a common condition that can lead to various complications, with gastroesophageal reflux cough (GERC) being one of the notable manifestations. Despite conventional therapies targeting acid suppression, recurrence and incomplete efficacy remain significant challenges. Tongjiang Hewei Decoction (THD), a traditional Chinese formulation, has shown clinical promise in alleviating GERD‐related symptoms. However, its therapeutic mechanisms in GERC remain unexplored. In this study, the airway hyperresponsiveness (AHR) guinea pig model was constructed by infusing hydrochloric acid into the lower esophagus. Transcriptome sequencing was used to identify THD‐related possible pathways in GERC. Lung resistance was measured to evaluate lung function. Hematoxylin–eosin staining, immunohistochemistry, real‐time fluorescence quantitative polymerase chain reaction, and western blotting were employed to assess airway remodeling. Airway smooth muscle cells were isolated to further investigate the effects of THD in vitro. In vivo assay indicated that THD reduced lung resistance and attenuated bronchial wall thickening, mucus hypersecretion, and inflammatory infiltration in a dose‐dependent manner. Mechanistically, THD suppressed ADAM33, RhoA/ROCK, and Epac1/Rap1 pathways in vivo, correlating with reduced α‐SMA and sm‐MHC expression. Transcriptomic analysis revealed that THD exerted its effects through the Epac1/Rap1 signaling pathway. The Rap1 activator reversed THD's anti‐AHR effects. In vitro, THD inhibited contractile protein synthesis via ADAM33 silencing, while ADAM33 overexpression abolished this effect. Collectively, THD alleviated GERC‐induced AHR through dual modulation of the ADAM33/RhoA/ROCK axis and Epac1/Rap1 signaling, providing novel mechanistic insights into its therapeutic potential. These findings position THD as a multifaceted candidate for GERC management, bridging traditional medicine with modern molecular pharmacology.