The Effect Acid-sensing Ion Channels On Esophageal Visceral Hypersensitivity

ObjectiveMany factors involved in the pathogenesis of gastroesophageal reflux disease(GERD).Aconventional acid penetration theory has been used to explain the mechanism that refluxatedo direct damage to esophageal mucosa by chemical stimulation leading the nerve endingexposure to acid environment, but much recent evidence does not support this theory.Inflammation and visceral nervous system dysfunction play a key role in the onset of GERD.It is known that acid excites sensory afferents in the esophagus by activating proton-gatedion channels including acid-sensing ion channels (ASICs). Inflammatory mediators in themucosa of the esophagus in patients with GERD can reduce acid-sensitive ion channelssignal transduction threshold, causing hypersensitive phenomenon.The different combinations of acid-sensing ion channel subunits contribute to dynamiccharacteristics, pH sensitivity and tissue distribution specificity. Current studies found thatexpression of ASIC1,2, and3mRNA was found in esophagus and dorsal root ganglia(DRG). Different subtypes of ASICs may during the onset of GERD plays differentrole.ASIC3make a critical positive contribution to mechanosensitiity and acid-sensitivity inthree out of four classes of visceral afferents. The presence of ASIC1appears to provide aninhibitory contribution to the ion channel complex. However, there is limited data availableregarding the role of ASICs in GERD. This study looked at different ASICs receptorsubunits in patients with GERD changes of expression of esophageal mucosa and evaluatesdifferent ASICs subunits expression changes and the correlation of patients with esophagealpain threshold changes.MethodsPatients with heartburn and/or regurgitation derived from primary care were presentedwith a six-item gastroesophageal reflux disease questionnaire (GerdQ) in the Chineselanguage. Patients with GERD-Q score greater than8points for endoscopic examination,according to the patients with clinical manifestations,(including symptoms, proton pumpinhibitor treatment response, etc.), endoscopic and pathologic examination results, theexperimental group: patients with reflux esophagitis (RE) under gastroscopy Los-Angeles-grade for class B or above in materials (group A) and near the affected area based on itsown control group Dcases; Los-Angeles-classification into A level in the place of drawing (group B);16normal volunteers with no symptoms of the control group (group C). Thecontrol group with the dentate line3cm for the standard, to return the subjects esophagealmucosa biopsy specimens.The expressions of ASIC1and ASIC3in esophageal mucosa were analyzed byimmunofluorescence and real-time PCR. We investigated the correlation of acid-sensing ionchannels and Inflammation Indexes, classical symptoms in GERD patients.ResultsThe histologic changes mainly include: squamous epithelial basal cell hyperplasia,basal layer thickening, different level of the squamous epithelial thickness of more than16%of the normal (no more than15%).Lamina propria inflammatory cell infiltration andepithelial foot extend, mucosa lamina propria nipple up bellows surface extension, morethan two-thirds of epithelial thickness (normal less than1/2).It was not clear pathologicalchanges in control.The mRNA expression was showed as follows. ASIC1mRNA expression of group Aas well as group B were higher than group D and group C(P＜0.05,group A36.527±34.912,group B21.242±14.325,group C4.404±2.938,group D5.413±4.215).ASIC3mRNA expression of group A was the greatest, followed with group B whileASIC3mRNA expressions of group C and D relatively low(P＜0.05, group A5.200±4.343,B1.137±0.660,C0.352±0.164, D0.419±0.349).The optical density of the ASIC1-immunostained sections and ASIC3-immunostainedsections of esophageal biopsies taken from4groups are showed below. ASIC1protein washigher in group A（0.107±0.012）and B（0.100±0.018）, and lower in group C（0.048±0.006）and D（0.053±0.007）(P<0.01). The optical densities of theASIC3proteinlevels was significantly greater in group A（0.075±0.006）and B（0.075±0.004）,and lighterin group C（0.055±0.007）and D（0.055±0.007）(P<0.01). ASIC1&ASIC3was positivelycorrelated with the typical symptoms of heartburn and Pearson correlation coefficientswere0.675,0.571, ASIC1&ASIC3was positively correlated with the typical symptoms ofchest pain, Pearson correlation coefficients were0.636,0.611, and no obvious correlationbetween reflux, degree of inflammation. ConclusionThe ASIC1and ASIC3were all up-regulated in GERD, which means ASIC1and ASIC3might play an important role in formation and keeping the visceral hypersensitivity.