Abstract
Neurogenic airway inflammation in chronic cough and bronchial asthma related to gastroesophageal reflux (GER) is involved in the esophageal–bronchial reflex, but it is unclear whether this reflex is mediated by central neurons. This study aimed to investigate the regulatory effects of the dorsal vagal complex (DVC) on airway inflammation induced by the esophageal perfusion of hydrochloric acid (HCl) following the microinjection of nuclei in the DVC in guinea pigs. Airway inflammation was evaluated by measuring the extravasation of Evans blue dye (EBD) and substance P (SP) expression in the airway. Neuronal activity was indicated by Fos expression in the DVC. The neural pathways from the lower esophagus to the DVC and the DVC to the airway were identified using DiI tracing and pseudorabies virus Bartha (PRV-Bartha) retrograde tracing, respectively. HCl perfusion significantly increased plasma extravasation, SP expression in the trachea, and the expression of SP and Fos in the medulla oblongata nuclei, including the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (DMV). The microinjection of glutamic acid (Glu) or exogenous SP to enhance neuronal activity in the DVC significantly potentiated plasma extravasation and SP release induced by intra-esophageal perfusion. The microinjection of γ-aminobutyric acid (GABA), lidocaine to inhibit neuronal activity or anti-SP serum in the DVC alleviated plasma extravasation and SP release. In conclusion, airway inflammation induced by the esophageal perfusion of HCl is regulated by DVC. This study provides new insight for the mechanism of airway neurogenic inflammation related to GER.
Highlights
Gastroesophageal reflux (GER) is one of the most common causes of chronic cough and is associated with severe asthma (Irwin et al, 1981, 1990; Klauser et al, 1990; Mello et al, 1996; Harding and Richter, 1997; Leggett et al, 2005; Lai et al, 2013); its pathogenesis is poorly understood
Data are expressed as the mean ± SD. ∗∗∗p < 0.001 compared with the other three groups; #p > 0.05 among the control, saline and sham groups; one-way analysis of variance (ANOVA) followed by LSD test
The results indicated that the nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus (DMV) neurons connecting to the airway were active, and substance P (SP) expression increased during hydrochloric acid (HCl) intra-esophageal perfusion
Summary
Gastroesophageal reflux (GER) is one of the most common causes of chronic cough and is associated with severe asthma (Irwin et al, 1981, 1990; Klauser et al, 1990; Mello et al, 1996; Harding and Richter, 1997; Leggett et al, 2005; Lai et al, 2013); its pathogenesis is poorly understood. Single acid perfusion into the distal esophagus induces microvascular leakage, which is suppressed by a neurokinin 1 receptor (NK1R) antagonist or by cutting the bilateral vagus, indicating that acid stimulation leads to the release of substance P (SP) and neurogenic inflammation (Hamamoto et al, 1997). We established a guinea pig model with GER by performing repeated esophageal HCl perfusion and observed increased plasma leakage and neuropeptides, such as SP, neurokinin A (NKA), and NKB in lung tissues (Liu et al, 2013), and the airway hyperresponsiveness and remodeling could be induced (Cheng et al, 2014). Acid perfusion in GER disease (GERD) patients worsens their cough (Ing et al, 1992; Ing and Ngu, 1999) These studies suggest that cough is closely associated with GER, and airway neurogenic inflammation could be induced by acid stimulation in the esophagus. Whether the esophageal-bronchial reflex and neurogenic inflammation of the airway are involved in the modulation of central nervous system (CNS) remains unclear
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