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Abstract

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.

Keywords

cough reflex gastroesophageal reflux-induced cough (GERC)microaspiration neurogenic inflammation neuropeptide

Introduction

Chronic cough is typically defined as a cough persisting for 8 weeks or longer.¹ This condition can arise from various etiologies, including upper airway cough syndrome, asthma, gastroesophageal reflux disease (GERD), eosinophilic bronchitis, and the use of angiotensin-converting enzyme inhibitors.^2,3 In GERD-related chronic cough, known as gastroesophageal reflux-related cough (GERC), epidemiological studies have shown a wide variation in its prevalence among patients with chronic cough of known causes, ranging from approximately 10% to 59%.⁴ Traditionally, the pathogenesis of GERC has been primarily based on the “acid injury theory,” which has established acid suppression therapy as the cornerstone of treatment.⁵ However, this theory faces multiple challenges in clinical practice: nearly half of the patients do not exhibit typical symptoms of acid reflux or heartburn;⁶ some patients respond poorly to potent acid suppression therapy;⁷ moreover, studies have confirmed that non-acidic or weakly acidic reflux can also trigger cough.^8,9 These pieces of evidence collectively suggest that, in addition to direct acid stimulation, other key mechanisms must be involved in the pathogenesis of GERC.

To explain these contradictions, clinical research has shifted toward more complex mechanistic models. Among them, the “neurogenic inflammation” pathway posits that refluxate from the esophagus can stimulate the vagus nerve, thereby inducing the release of airway neuropeptides and inflammation via a reflex mechanism, without the necessity for direct aspiration of the material.^10,11 Simultaneously, research on the “microaspiration” mechanism has deepened our understanding of the direct damage to airway mucosa caused by components such as pepsin.^12,13 These two mechanisms may act synergistically, yet the specific interactive network between them remains to be systematically elucidated.

Therefore, the core objective of this review is to elucidate the key pathogenic mechanisms of GERC. The focus will be on delineating the initiation pathways and molecular foundations of “microaspiration” and “neurogenic inflammation,” and on deeply analyzing how they mutually promote each other through inflammatory mediators and neural signals, collectively driving the chronicity of cough. This article aims to explain the occurrence and persistence mechanisms of GERC at a mechanistic level, thereby providing a solid theoretical basis for the innovation of therapeutic strategies.

The mechanism of GERC

GERC is primarily attributed to the interplay between microaspiration and neurogenic inflammation. This process encompasses complex mechanisms, including the diffusion of various inflammatory mediators and the activation of neuropeptides (Figure 1).

Figure 1.

The positive feedback mechanism loop of GERC.

GERC consists of four primary components: anatomical damage, neural sensitization, inflammatory spread, and mechanical disruption, which collectively establish a complete positive feedback loop. Anatomical injuries can simultaneously induce neural sensitization and promote the spread of inflammation. Prolonged chronic inflammation can irritate exposed nerve endings. The neuropeptides produced through neural sensitization not only stimulate mast cells to propagate inflammation but also exacerbate the cough reflex, thereby aggravating the reflux of gastric acid and pepsin, leading to more severe anatomical damage.

Microaspiration

Conditions of generation

Microaspiration is the process by which a small amount of gastric contents or pharyngeal secretions breaches the protective barriers of the pharynx and enters the airway, typically associated with GERD. The occurrence of microaspiration is primarily linked to an imbalance between the height of reflux and the defensive function of the pharynx. When transient lower esophageal sphincter relaxation (TLESR) occurs, and the basal pressure of the upper esophageal sphincter (UES) decreases to below 40 mmHg, the combined effect of these two factors allows the refluxate to surpass the conventional reflux boundary, consequently leading to laryngopharyngeal reflux (LPR).^14,15 Research indicates that patients with predominantly upright reflux are more susceptible to microaspiration.¹⁶ LPR shares similar symptoms with gastroesophageal reflux, suggesting that it does not present a specific clinical syndrome.¹⁷ However, the risk of microaspiration significantly increases during the night. During nocturnal sleep, the genioglossus muscle reflex is inhibited, and the protective reflexes of the pharynx are weakened, which facilitates microaspiration.¹⁸ In addition, the epithelium of the pharynx lacks the carbonic anhydrase buffering system found in the esophageal mucosa, rendering it significantly less resistant to gastric acid and pepsin compared to the esophagus. Even weak acid reflux (pH 4–7) can disrupt intercellular junctions in the squamous epithelium of the laryngeal mucosa, exposing nerve endings.

Direct damage

The direct injury caused by microaspiration is primarily manifested as the synergistic damaging effect of gastric acid and pepsin. The pH of gastric acid is extremely low, exhibiting strong corrosive properties. When gastric acid is aspirated into the airway, it not only directly damages the epithelial cells of the airway mucosa but may also lead to local inflammatory responses and airway remodeling.¹⁹ A previous study on adult canine models found that all animals exhibited reflex laryngospasm when exposed to solutions with a pH below 2.5.²⁰ Although the inhalation of trace amounts of gastric acid cannot directly cause chemical pneumonia, it can activate the transient receptor potential vanilloid subfamily member 1 (TRPV1) and acid-sensing ion channels (ASICs), thereby triggering the transient cough reflex.²¹

Pepsin exhibits strong activity in environments with a pH value below 5.²² It can disrupt the tight junctions of respiratory epithelial cells by degrading the mucin layer of the airway mucosa and intercellular junction proteins, such as claudin-1.²³ As an exogenous antigen, pepsin is recognized by airway dendritic cells, which promotes Th2-type inflammatory responses, leading to the release of cytokines such as IL-4 and IL-13, and inducing eosinophil infiltration.²⁴ Recent studies have demonstrated that proteases with cysteine-like proteolytic activity can activate cutaneous sensory nociceptive neurons.^25,26 Specifically, pepsin enhances the expression of TRPV1 receptors and lowers the activation threshold of cough receptors.

Studies utilizing 24 h esophageal pH-impedance monitoring have demonstrated that up to 40% of asymptomatic subjects exhibit non-acid reflux.²⁷ In patients with non-acid GERD, research has identified a significant accumulation of non-acid refluxate—primarily liquid—in the proximal esophagus and pharyngeal region.²⁸ These non-acidic reflux activities not only contribute to the thickening of the lower esophagus and local structural and functional abnormalities but also facilitate the upward movement of reflux into the upper esophagus. Furthermore, non-acid reflux can stimulate mechanosensitive receptors, thereby inducing cough via A-delta fibers.²⁹ Cough induced by non-acid reflux is also linked to cough reflex hypersensitivity, which is attributed to elevated concentrations of substance P and mast cell tryptase.³⁰ Consequently, neuroinflammation triggered by low-position reflux and pharyngeal airway inflammation resulting from prolonged proximal reflux stimulation may lead to damage of the airway epithelium, thereby exposing cough receptors.³¹ This exposure can promote the remodeling and proliferation of cough receptors, ultimately resulting in increased airway sensitivity, which may directly precipitate coughing.

Chemical inflammation response

The chemical inflammatory response induced by microaspiration exhibits a cascade effect. It is initially triggered by direct damage from gastric acid and pepsin. Gastric acid activates TRPV1 receptors in the airways, eliciting an immediate cough reflex, while pepsin degrades the mucus layer, leading to shedding of epithelial cells.^21,23 Furthermore, microaspiration facilitates the infiltration of inflammatory cells and the release of cytokines. The damaged airway epithelium releases chemokines such as IL-8 and TNF-α, which recruit neutrophils and monocytes, subsequently leading to the release of proteases and oxygen-free radicals.³² The interplay between the infiltration of inflammatory cells and the release of cytokines creates a vicious cycle that exacerbates airway damage and dysfunction. Ultimately, recurrent microaspiration can instigate long-term chronic inflammation. Persistent chronic inflammation may result in progressive structural changes, including bronchial epithelial metaplasia, thickening of the basement membrane, and goblet cell hyperplasia.³³ Consequently, patients often present with a persistent dry cough accompanied by excessive mucus secretion.

Neurogenic inflammation

Anatomical basis

Neurogenic inflammation refers to the inflammatory response induced by neuropeptides released from sensory nerve endings, primarily triggered through the esophageal-tracheal-bronchial reflex in GERC.³⁴ The esophagus and trachea both originate from the embryonic foregut and share a common vagal pathway.³⁵ Acid receptors in the lower esophagus, transmitted via the vagus nerve, converge with airway cough receptors in the nucleus tractus solitarius (NTS) of the brainstem, forming the anatomical basis of this reflex. This convergence allows acid stimulation signals from the esophagus to undergo signal processing, amplification, or misinterpretation through the central nervous system, primarily the NTS, ultimately activating the cough reflex center and inducing coughing, even in the absence of direct airway stimulation. The key afferent fibers responsible for this reflex are the vagal C fibers originating from the nodose ganglion. The vagal afferent fibers of the esophagus are primarily unmyelinated C fibers, which express TRPV1 receptors (sensitive to capsaicin) and are highly sensitive to acid and inflammatory mediators.³⁶ TRPV1, a non-selective cation channel, increases ion channel opening upon binding with capsaicin, leading to the release of neuropeptides from nerve endings, which directly or indirectly induce coughing.³⁷ Among these, in vagal neurons expressing voltage-gated sodium channels (Nav1.8), G protein-coupled receptors (GPCRs) mediate neurotransmitter signals transmitted from the nodose ganglion to the NTS.³⁸ In addition, vagal C fibers can also be activated by endogenous mediators related to inflammation, such as bradykinin, adenosine, histamine, and 5-hydroxytryptamine (5-HT).³⁹

Neuropeptide

Neuropeptides are biologically active molecules synthesized and released by neurons, playing a crucial role in neuro-immune interactions. Among these, substance P (SP), neurokinin A/B (NKA/B), and calcitonin gene-related peptide (CGRP) serve as key effector molecules, all released from the nerve endings of C fibers.

Both SP and NKA/B are members of the tachykinin (TAC) family. TAC signaling is primarily mediated by neprilysin (NEP), and the absence of this enzyme results in increased vascular permeability and triggers inflammatory responses. Among these tachykinins, SP binds to the neurokinin 1 receptor (NK1R), while NKA and NKB specifically bind to the neurokinin 2 receptor (NK2R) and neurokinin 3 receptor (NK3R), respectively.^40,41 All three types of NKR are expressed in airway smooth muscle (ASM) cells, suggesting that NKR plays a significant role in ASM contraction.⁴² In ovalbumin (OVA)-sensitized rats, the release of SP and NKA from the nerve C fiber terminals leads to an increase in body temperature, which subsequently induces bronchoconstriction.⁴³ As a potent pro-inflammatory factor, SP, upon binding to NK1R, activates small-diameter nerve fibers, thereby enhancing the cough reflex.⁴⁴ SP increases the calcium ion concentration in ASM cells by downregulating the expression of the sodium-calcium exchanger (NCX) protein and the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), which further enhances bronchial contraction.^45,46 SP increases vascular permeability, thereby exacerbating airway inflammation and mucosal edema.⁴⁷ SP can upregulate the expression of the MUC5AC gene by activating the NF-kB pathway, leading to a state of airway mucus hypersecretion.⁴⁸ The SP released by sensory neurons can act on mast cells to produce inflammatory mediators such as histamine, TNF-α, and vascular endothelial growth factor (VEGF).⁴⁹ These mediators further stimulate cough receptors, amplifying the cough reflex. Moreover, mast cells can release tryptase, which activates protease-activated receptor-2 (PAR-2) on neurons, further mediating the release of SP and inducing neurogenic inflammation.⁵⁰

CGRP is a neuropeptide composed of 37 amino acids, existing in two subtypes, α and β, which exhibit high similarity (>90%) in homology and biological activity, differing by only three amino acids in humans.⁵¹ Among these, αCGRP is primarily distributed in the central nervous system and the peripheral nervous system, while βCGRP is mainly present in the enteric nervous system and is synthesized by pulmonary neuroendocrine cells (PNEC) in the airways.^51,52 CGRP can exacerbate airway inflammation by dilating blood vessels and increasing vascular permeability, thus promoting the infiltration of inflammatory cells.⁵³ CGRP can inhibit macrophage apoptosis to some extent, prolonging the survival time of inflammatory cells.⁵⁴ Studies have shown that CCL17 can amplify the vascular component of the inflammatory response by stimulating epithelial cells to release CCR4.⁵⁵ Furthermore, CGRP regulates the Th9 response by inducing the expression of PU.1, a transcription factor of Th9 cells, and the production of IL-9.⁵⁶ Eosinophils can also promote the synthesis of leukotriene C4 by recruiting CGRP, thereby triggering a Th2 response.⁵²

Peripheral and central sensitization

Reflux substances, including gastric acid, pepsin, and bile acids, irritate the mucosa of the lower esophagus, thereby activating nociceptors such as TRPV1 and TRPA1.⁵⁷ Concurrently, esophageal distension, particularly during significant reflux of gastric contents, stretches the nerve endings, thereby activating mechanosensitive receptors. The release of adenosine triphosphate (ATP) from damaged mucosal cells activates P2X3 receptors on sensory nerve endings in the airways, mediating rapid depolarization of the nerves, which, in turn, sensitizes peripheral sensory neurons.⁴⁷ Following stimulation of the esophageal mucosa, the vagus nerve C fibers release neuropeptides, including SP and CGRP. These released neuropeptides induce mast cell degranulation, resulting in the release of histamine, tryptase, and other substances that lead to local tissue edema and the accumulation of inflammatory factors.^49,50 Persistent inflammatory states may cause prolonged exposure of nerve endings to irritants, resulting in a reduced cough threshold. The nerve growth factor (NGF) released by the stimulation of vagal nerve endings due to esophageal reflux enters the airway via the bloodstream, binds to the TrkA receptor on sensory neurons, and enhances TRPV1 transcription through the p38 MAPK pathway.⁵⁹ Following an increase in the number of TRPV1 channels, there is an excessive sensitivity to stimuli such as acid, where even mild reflux can trigger a strong cough signal. Furthermore, TRPA1 is also closely associated with airway inflammation, and its upregulation may exacerbate allergic responses in the airways.⁶⁰ The upregulation of these ion channels not only heightens airway excitability but may also worsen the frequency and intensity of coughing.

Gastric acid and pepsin stimulate the lower esophagus, activating vagal C fibers, whose afferent signals project to the NTS in the medulla oblongata via the nodose ganglion.⁶¹ Persistent reflux stimulation results in an increased release of glutamatergic neurons in the NTS region, which activates N-methyl-D-aspartate (NMDA) receptors, subsequently triggering synaptic long-term potentiation (LTP) through calcium ion influx and leading to a permanent increase in neuronal sensitivity.^58,62 Among these processes, calcium/calmodulin-dependent kinase II (CaMKII) plays a crucial role in LTP.⁶³ Microglia can induce neuronal damage by releasing reactive oxygen species (ROS) and pro-inflammatory factors.⁶⁴ Astrocytes decrease the synthesis of inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA), resulting in a decline in central inhibitory function.⁶⁵ Furthermore, during the regulatory process of the higher brain centers, the cerebral cortex (including the anterior cingulate cortex and insula) exhibits a reduced threshold for the perception of cough signals, complicating the suppression of coughing.⁶⁶ The periaqueductal gray (PAG) of the midbrain also diminishes the function of the descending inhibitory pathway in the medulla oblongata, thereby hindering the effective termination of the cough reflex.⁶⁷

Long-term peripheral stimulation can induce synaptic remodeling in the NTS, resulting in a sustained increase in the sensitivity of the cough center and leading to a persistent and exaggerated cough reflex. Following central sensitization, descending pathways, such as those originating from the dorsal raphe nucleus, release serotonin 5-hydroxytryptamine (5-HT), which activates peripheral vagal nerve endings, thereby exacerbating peripheral sensitization.⁶⁸ In addition, centrally released SP and CGRP are retrogradely transported to the periphery, further exacerbating neurogenic inflammation and perpetuating a vicious cycle of “inflammation-sensitization-cough.”

Conclusion

The pathogenesis of GERC is characterized by a synergistic interplay between microaspiration and neurogenic inflammation. These processes are not isolated but rather create a positive feedback loop exemplified by the “injury-inflammation-neural sensitization-further injury” pattern. Microaspiration disrupts the tight junctions of the esophageal epithelium, facilitated by gastric acid and pepsin, which exposes deep cough receptors directly to the refluxate. This process initiates a cross-organ inflammatory signaling cascade, primarily involving IL-8 and TNF-α. The vagus nerve-mediated esophago-tracheo-bronchial reflex, through the release of neuropeptides such as SP, activates the mast cell-tryptase-PAR-2 axis, further compromising the epithelial barrier. Central sensitization results in an enhanced cough reflex; during severe coughing episodes, the thoraco-abdominal pressure gradient increases, thereby promoting the reflux of gastric contents. Consequently, the disruption of the mucosal barrier due to microaspiration can heighten the sensitization of nerve endings, while the mediators released during neurogenic inflammation may exacerbate reflux susceptibility, culminating in a self-reinforcing pathological cycle. In the future, it is conceivable that relevant mechanisms may facilitate the transition of GERC from symptomatic treatment to more precise, mechanism-targeted therapy.

Footnotes

Acknowledgements

None.

Authors’ note

The figure in the manuscript was created by the author and was not subject to copyright issues.

Declarations

ORCID iDs

Fang Yi

Ming-Tong Lin

Zhe Chen

Artificial intelligence disclaimer

No artificial intelligence tools were used in writing this manuscript.

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, et al. Defensive and emotional behavior modulation by serotonin in the periaqueductal gray. Cell Mol Neurobiol 2022; 43: 1453–1468.

Gastroesophageal reflux-induced cough: the positive feedback loop of microaspiration and neurogenic inflammation

Abstract

Keywords

Introduction

The mechanism of GERC

Microaspiration

Conditions of generation

Direct damage

Chemical inflammation response

Neurogenic inflammation

Anatomical basis

Neuropeptide

Peripheral and central sensitization

Conclusion

Footnotes

Acknowledgements

Authors’ note

Declarations

ORCID iDs

Artificial intelligence disclaimer

References