The Clinical Study Of IL-1β In The Esophageal Motility Of NERD And The Basic Research Of IL-1β In Visceral Hypersensitivity Following Exposure To Post Traumatic Stress Disorder

Background and objective:Non-erosive reflux disease(NERD)refers to patients who experience reflux related symptoms,but where esophageal mucosal lesion or Barrett’s esophagus cannot be detected by standard endoscopic techniques.NERD is the most common clinical gastroesophageal reflux entity,accounting for about 50%-70% of gastroesophageal reflux disease(GERD).NERD affects people’s daily life and work.In recent years,associated with changes in people’s lifestyle and eating habits,the incidence of NERD has increased.The incidence in Western Europe and North America is higher than that in Asia in general.The pathogenesis of NERD is complex and has not been fully investigated and understood.Clinically,there is a lack of effective therapeutic drugs that can eradicate the patient’s symptoms,Visceral hypersensitivity and pain sensitization was thought to be one of the pathophysiological mechanisms of visceral pain in NERD and a cause of the symptoms in these patients.The exact mechanism of visceral hypersensitivity in the NERD patients has not been fully understood.Scientists have proposed that the presence of inflammation in NERD patients might be earlier than the presence of microscopic changes in the esophageal mucosa.It has been suggested that cytokines and inflammatory mediators may mediate epithelial immune inflammation and the esophageal hypersensitivity.Recent studies have shown that interleukin-1β(IL-1β)and its gene polymorphism were closely related to the occurrence of NERD and visceral hypersensitivity.However,previous studies have regarded NERD as one disease entity where the differences of the pathogenesis between NERD patients with different symptom subtypes were not further differentiated.In this study,we detected the IL-1β content,measured high resolution manometric esophageal pressure profilesand(HRM)monitored 24 h p H in the distal esophagus to explore the effects of IL-1β and esophageal motility on the pathogenesis of visceral hypersensitivity in NERD patients.Methods:1.Two hundred and fourteen cases of NERD patients were randomly selected who had visited the Digestive System Department of Daping Hospital,Third Military Medical University from August 2012 to 2015 December.Q GERD symptom scale,upper gastrointestinal endoscopy,and high-resolution manometry(HRM)was used to diagnose NERD and for subtyping the symptoms.According to the Q GERD symptom ≧scale 8 points,exclusion criteria were esophageal and gastric mucosal damage as observed with endoscopy.Based on the above and whether or not there was typical heartburn and acid reflux symptoms and other NERD symptoms,the patients were divided into a typical NERD group and an atypical NERD group and normal control group.2.Under direct vision of upper gastrointestinal endoscopy,a biopsy of antrum tissue was done.Enzyme linked immunosorbent assay(ELISA)was used to detect the IL-1β content to investigate the possible pathogenesis of IL-1β in the two subtypes of NERD.3.HRM was used to monitor the esophageal dynamics characteristics of the subtypes of NERD patients,intending to study characteristics difference in esophageal motility related to different symptoms in the subtypes of NERD patients and the possible pathogenesis.4.24 h p H monitoring technique was used to analyze the acid reflux in patients with subtypes of NERD with the intention to explore characteristics of acid reflux.Result:1.The expression of IL-1β related to the typical symptoms and atypical symptoms of NERD patients: compared with the atypical symptom group(n=27),the expression of IL-1β in the typical symptom group(n=43)was significantly decreased[(75.26±7.20)pg/ml vs.(107.22±13.07)pg/ml,P=0.039];Compared with the control group(n=58),the expression of IL-1β in the typical symptom group(n=43)and the atypical symptom group(n=27)were significantly increased[(107.22±13.07)pg/ml vs.(75.26±7.20)pg/ml vs.(51.88±2.90)pg/ml,PCT =0.004,PCA=0.000].Compared with the control group(n=58),the expression of IL-1β in NERD patients(n=70)were significantly increased [(87.59±6.94)pg/ml vs.(51.88±2.90)pg/ml,P=0.002)].2.The different characteristics of esophageal dynamics between typical and atypical NERD patients: compared with the atypical symptom group(n=39),the esophageal sphincter(LES)resting pressure of typical symptom group(n=47)was significantly lower [(15.79±1.21)mm Hg vs.(20.68±1.64)mm Hg,P=0.006] and the LES residual pressure of the typical symptom group was significantly decreased [(5.80±1.16)mm Hg vs.(10.42±1.20)mm Hg,P=0.005].Esophageal body peristalsis,LES total length,LES intra-abdominal length,upper esophageal sphincter(UES)resting pressure and residual pressure were not different between the typical symptom group and atypical symptom group(P > 0.05).3.The 24 h esophageal p H monitoring of typical and atypical NERD patients: no obvious statistical difference was found for the De Meester score,acid reflux and reflux event between the atypical symptom group(n=24)and typical symptom group(n=25)(P > 0.05).Conclusions:1.The Q GERD scale and upper gastrointestinal endoscopy were used to make a preliminary diagnosis of NERD.According to the clinical symptoms of NERD patients were divided into two groups and the IL-1β content was determined for the typical symptoms and atypical symptoms NERD groups and control group.The IL-1β content among the three groups were significantly different,suggesting that IL-1β is involved in the onset of NERD.2.HRM was used to monitor the esophageal pressure dynamics in the NERD subtype patients.The characteristic differences in esophageal motility between the two patient groups mainly lie in the decrease of LES resting pressure and LES residual pressure.This indicates that differences of LES pressure and function were one of causes of the different symptoms and the difference in LES pressure and function may be part of the pathogenesis of NERD.3.The 24 h esophageal p H monitoring showed that there was no obvious difference between the two NERD groups.This indicated that they were similar in acid reflux.Hence,different esophageal susceptibility to acid may be the reason that various NERD subtypes have different symptoms and that NERD patients have visceral hypersensitivity.Background and objective:Post traumatic stress disorder(PTSD)refers to the mental disorder after encountered or resisting a major stress event.Symptoms of PTSD usually occur several days or even months after encountered the trauma.The course can be as long as several years,or even for lifetime.PTSD is characterized by high prevalence,long duration of disease and poor curative effect.It is difficult to cure in the clinic.The morbidity of irritable bowel syndrome and bladder pain syndrome after PTSD showed an upward trend with visceral hypersensitivity under the condition of PTSD.It was also observed that IBS and GERD usually were associated and accompanied each other in PTSD patients.These factors seem associated with the diversification of symptoms in these patients.Previous research of visceral hypersensitivity in PTSD mainly focused on the brain.Recently,studies suggested that the spinal cord and peripheral level played an important role for the formation and maintenance of stress-related visceral hyperalgesia.These topics have gradually become the hot spot of the field.However,the exact molecular mechanism and control measures of visceral hypersensitivity under PTSD are largely unexplored.IL-1β is an effective cell activating agent and multifunctional cytokine secreted by activated monocytes or macrophages.It played an important role in the signal transduction of neurological damage,immune response and visceral hypersensitivity and hyperalgesia.Studies showed that activated astrocytes in the dorsal horn of the spinal cord can generate and release large amounts of IL-1β.Therefore,It is important to explore the mechanism of IL-1β in visceral hypersensitivity in PTSD.The aim was to provide an important theoretical basis and a new way for the clinical prevention and treatment of visceral hypersensitivity related to PTSD.Methods: Thirty-two adult female SD rats were randomly divided into three groups: a normal control group(n=11),a PTSD group(n=11)and a PTSD+Ceftriaxone Sodium(CTX)group [pretreated with ceftriaxone(CTX),n=10].The animal model of PTSD was established by using single-prolonged stress(SPS)combined with electric foot shock.Expression of the spinal cord IL-1β and the effect of CTX on it was evaluated by immunofluorescence seven days after modeling.Results: The expression of IL-1β significantly increased in the PTSD group as compared with that of the control group [(19.55±1.60)vs.(39.07±1.81),P<0.001] whereas the expression of IL-1β significantly decreased in the PTSD+CTX group compared with that of the control group [(19.55±1.60)vs.(9.26±0.48),P<0.001].The expression of IL-1β significantly decreased when being treated with CTX compared with that of PTSD group p(39.07±1.81)vs.(9.26±0.48),P<0.001].Conclusions:High expression of IL-1β in the visceral hypersensitivity of PTSD,indicating that the IL-1β may take part in the formation of visceral hypersensitivity following exposure to PTSD-like stress.CTX may exert an effect on resistance to visceral hypersensitivity by directly down-regulating the expression of IL-1β in the spinal cord.It might prove to be an effective strategy for interfering with the visceral hypersensitivity after exposure to PTSD.