Gastroesophageal reflux-related cough (GERC) is a common etiology of chronic cough, characterized by a complex pathogenesis. The limited efficacy of conventional acid suppression therapy suggests the presence of critical mechanisms that extend beyond mere gastric acid irritation. This review systematically explores the interaction between the two core pathways—“microaspiration” and “neurogenic inflammation”—in the context of GERC, aiming to elucidate their synergistic pathogenic mechanisms. On one hand, the gastric contents involved in microaspiration (such as gastric acid and pepsin) directly damage the airway mucosal barrier, activating local chemical inflammatory responses and specific receptors like transient receptor potential vanilloid subfamily member 1 (TRPV1). On the other hand, esophageal reflux can trigger a reflex arc mediated by the vagus nerve, prompting airway sensory nerves to release neuropeptides such as substance P, thereby initiating neurogenic inflammation and ultimately leading to heightened cough hypersensitivity. These two pathways do not exist in isolation; rather, they constitute a critical “injury-sensitization-reinjury” positive feedback loop: inflammation induced by micro-aspiration can sensitize sensory nerves, exacerbating neural reflexes; conversely, the severe cough resulting from neurogenic inflammation elevates intra-abdominal pressure, further promoting reflux and aspiration. A deep understanding of this interactive mechanism not only provides a comprehensive mechanistic basis for explaining refractory GERC but also lays the theoretical groundwork for developing novel combined therapeutic strategies that target both mucosal protection and neural modulation.
Rui et al. (Sun,) studied this question.