| Background Stress related mucosal disease(SRMD),also named stress ulcer,acute erosive gastritis or acute hemorrhagic gastritis,refers to acute gastrointestinal erosion or even ulceration caused by severe trauma,large surgery,critical illness and other serious stress conditions.Common diseases in intensive care unit,such as burns,craniocerebral trauma,severe systemic infection and cardiopulmonary cerebral resuscitation,are stressors of gastric mucosal lesions.Endoscopic examinations on the critically ill patients that have stayed in ICU over 72 hours showed that 75%-100%of them exhibited varying degrees of gastric mucosal lesions and 1%-6%of them had the symptoms of upper gastrointestinal bleeding.The pathological stage of SRMD is related to the severity of ICU patients.At present,animal models and in vitro experiments have reported on the pathogenesis of SRMD.It is believed that gastric mucosa plays an important role in the physiological function of the stomach.It acts as a barrier to the stomach and protects cells that settle in deep layers.It also fights gastric acid and pepsin secreted by the chief cells and parietal cells,and prevents stomach acid and other substances ingested from damage to the gastric mucosa.Although the gastric mucosa is continuously exposed to harmful environments,it still maintains the functional and structural integrity.The traditional view is that the gastric mucosal barrier is composed of tight junctions between epithelial cells,as well as the immediate mucus layer.Mucosal blood flow also plays an important role in maintaining the gastric mucosal barrier function.Other factors,such as the production of nitric oxide(NO)and cyclooxygenase and the activity of antioxidant factors,such as superoxide dismutase(SOD),are also involved.The mucosal immune system is widely distributed under the mucosa of the human body and is also part of the mucosal defense mechanism.The animal models of bound water immersion and in vitro experiments confirmed that under stress,oxidative stress,ischemia-reperfusion injury,endogenous nitric oxide and less mucosal blood flow,may be the causes of SRMD.Till now,although several animal models and in vitro experiments have been conducted to study the pathogenesis of SRMD,there are few clinical studies on the pathogenesis of SRMD in critically ill patients.In clinical practice,the occurrence of SRMD is followed by critically ill,complicated conditions and many influencing factors,so clinical research is difficult to carry out.However,in real and complex clinical situations,it is important to study the changes in the indicators of gastric mucosal barrier in patients with SRMD,and which role they play in the development of SRMD.So far,the significance of some indicators has been studied in the experiment of water-immersion stress animal models,for example,malondialdehyde(MDA)is an indicator of oxidative stress,and SOD reflects the performance of tissue antioxidant enzymes.NO may play a dual role in the pathogenesis of gastric ulcer.But some problems should be further observed.In particular,it is necessary to conduct a comprehensive study on the barrier state of gastric mucosa under stress in a clinical situation,and the functional changes of mucosal immunity in the pathogenesis of SRMD are also worthy of studying.Because the pathogenesis of SRMD is not completely clear,clinical treatment can only protect gastric mucosa by inhibiting gastric acid.It is found that ICU patients with SRMD will aggravate the original disease,which will increase the mortality of patients.Due to unsatisfactory results,in clinical work,acid-suppressing drugs are often used to prevent SRMD in critically ill patients,especially ICU patients,thus increasing the incidence of pneumonia.However,not all critically ill patients will have a concurrent SRMD,and there are no accurate clinical indicators to predict SRMD.How to screen high-risk groups and avoid over-medication for low-risk patients is also of great significance for improving the diagnosis and treatment of critically ill patients and promoting the rational allocation of medical expenses.This study included patients admitted to the ICU as a research object,using gastroscope-assisted catheterization and other opportunities to retain the patient's gastric mucosa and blood samples to detect indicators related to the pathogenesis of SRMD,including Claudin3 of tight junction proteins,transforming growth factor-?1(TGF-?1),MDA,SOD,IL1? and IL10 that reflects the mucosal immune function,mast cells and other indicators whose functions are not fully defined,such as inducible nitric oxide synthase(iNOS)and ischemia modified albumin(IMA).Patients with acute cerebral hemorrhage combined with stress ulcer bleeding is a special case of SRMD.Their blood lipids and inflammation indicators are investigated.This study attempts to study the pathogenesis of SRMD more closely related to clinical scenarios and to find sensitive clinical indicators that reflect the risk of onset.Objective1.To investigate the pathogenesis of SRMD by studying indicators related to gastric mucosal barrier function in high-risk populations of SRMD.2.To research the changes of the immune function of SRMD and find out the clinical sensitive indicators reflecting the risk of SRMD by investigating indicators related to mucosal immune function in high-risk populations of SRMD.3.To explore the relationship among APACHE ? score,ET-1,TNF-a and blood lipids in patients with acute cerebral hemorrhage complicated with stress ulcer.Method1.Patients who were admitted to the ICU of Tai'an Central Hospital from December 2015 to August 2016 were included in the case group for gastroscopy and diagnosis of SRMD for various reasons within 72 hours of admission to the ICU.Healthy volunteers were recruited as a control group.The disease severity of patients in ICU was evaluated by the Acute Physiology and Chronic Health Evaluation(APACHE)? score.The severity of gastric mucosal lesions was assessed by pathological damage score after HE staining of biopsy mucosa.Mast cell counts were performed on the gastric mucosal tissue sections after toluidine blue staining.Serum MDA was detected using the thiobarbituric-acid-reactive substance method.Serum SOD and IMA were determined by SOD substrate method and free cobalt colorimetric method respectively.Claudin-3 in the gastric mucosa was assessed by Western blot.The levels of IL1?,IL10,transforming growth factor(TGF)?1 and iNOS in mucosa were detected by immunohistochemistry.The level of serum C-reactive protein(CRP)was detected by latex immunoturbidimetry.2.Patients with acute cerebral hemorrhage complicated with stress ulcer bleeding were selected as observation group,and other patients with simple acute cerebral hemorrhage were included in control group.The APACHE ? score,ET-1,TNF-a,total cholesterol(TC),triglyceride(TG),high density lipoprotein-cholesterol(HDL-C)and low density lipoprotein-cholesterol(LDL-C),BUN,Cr,and MDA were compared between the two groups.According to the APACHE ? score,they were divided into group ?(score greater than or equal to 20)and group ?(score greater than 10 scores and less than 20),and ET-1,TNF-a,TC,TG,HDL-C and LDL were compared between the two groups.The correlations between APACHE ? score and blood lipid factor,ET-1 and TNF-? were analyzed.Results1.A total of 38 patients with SRMD were enrolled,including 18 males and 20 females with an average age of(47.6±6.3)years old.The control group recruited 15 healthy volunteers,including 7 males and 8 females,with an average age of(47.0±5.6)years old.There was no significant difference in age and gender between the case group and the control group.A total of 53 patients with acute cerebral hemorrhage complicated with stress ulcer hemorrhage were enrolled,including 23 males and 30 females,with an average age of(49.8±4.5).50 patients with simple cerebral hemorrhage were investigated,including 23 males and 27 females,with an average of(51.2±4.8)years old.There was no statistical difference in the general data between the two groups.2.The APACHE ? score of the case group was(14.87± 5.6),and since the volunteers in the control group were healthy,no APACHE II score was made.The pathological injury score of HE staining of gastric mucosa in the control group was(1.04±0.60).The pathological injury score of the case group was(2.92±1.08),and the difference of pathological injury scores between the two groups was statistically significant(P = 0.000).The mean values of MDA and IMA in SRMD patients were higher than those in the controls(MDA,patients,4.73±2.89 nmol/ml vs.controls,0.55±0.34 nmol/ml,P=0.000;IMA,patients,93.61±10.78u/ml vs.controls,59.07±7.41 u/ml,P=0.000),while the mean values of SOD in the patients were significantly lower than those in the controls(patients,89.66±12.85 u/ml vs.controls,148.73±13.50,P = 0.000).The iNOS expression in SRMD patients were higher than those in the controls(patients,0.1183±0.0173 vs.controls,0.0578±0.0031 P = 0.034)while the expression of TGF ?1 and claudin-3 in the patients were lower than those in the controls(TGF?1,patients,0.1071±0.0076 vs.controls,0.1532±0.0069 P=0.001;claudin-3,patients,0.12±0.05 vs.controls,0.95±0.61.P= 0.000).3.The counts of gastric mucosal mast cells and the number of mast cell degranulation and the percentage of degranulated mast cells in the case group were significantly higher than those in the control group(patients,76.84±19.54 vs.control,35.00±17.32,P=0.000;patients,39.26±15.80 vs.controls,6.40±3.62,P=0.001;patients,0.49±0.13 vs.controls,0.18±0.05,P=0.000).The differences had statistical significance.The expression levels of IL1? in SRMD patients were significantly higher than those in the control group(patients,0.0430±0.0044 vs.controls,0.0245±0.0011,P=0.012),and the difference was statistically significant.The serum CRP level in the case group was significantly higher than that in the control group(patients,128.83±116.26 u/ml vs.controls,1.56±1.19 u/ml P=0.000).4..APACHE ? score was positively correlated with pathological damage score(r=0.639,P = 0.000),levels of MDA(r = 0.743,P = 0.000),IMA(r = 0.353,P = 0.030)and iNOS(r = 0.324,P = 0.048),but negatively correlated with the level of SOD(r =-0.392,P = 0.015).MDA was positively correlated with IMA(r = 0.380,P = 0.018),but negatively correlated with claudin-3(r =-0.377,P = 0.020).The expression of mucosal IL1? in the case group was positively correlated with APACHE ? score,pathological damage score and serum MDA level(r=0.628,P=0.000;r=0.450,P=0.005;r=0.415,P=0.010).Mast cell count was positively correlated with APACHE II score and serum MDA level(r=0.464,P=0.003;r=0.477,P=0.002).The number of degranulated mast cells in gastric mucosa was positively correlated with APACHE ?score,pathological damage score,serum MDA level and mucosal IL1? expression(r=0.553,P=0.000;r=0.349,P=0.032;r=0.567,P = 0.000;r = 0.359,P = 0.032).The percentage of mast cell degranulation in gastric mucosa was positively correlated with APACHE II score,serum MDA level and mucosal IL1? expression(r=0.508,P=0.001;r=0.475,P=0.003;r=0.342,P=0.036).Serum CRP level was positively correlated with APACHE II score,pathological damage score,and MDA(r=0.585,P = 0.000;r=0.463,P=0.003;r=0.522,P=0.001).5.The blood lipid index TG,APACHE ? score,ET-1,TNF-?,renal function index BUN and CR,mortality,and MDA in the observation group were significantly higher than those in the control group(TG,observation group,118.65±11.53 mg/dl vs.control group,85.21±7.89 mg/dl,P=0.000,APACHE ?,observation group,26.54±2.65 vs.control group,14.45±1.32,P=0.000,ET-1,observation group,119.31±10.86 pg/ml vs.control group,100.32±9.56 pg/ml,P=0.004,TNF-?,observation group,1.03±0.12g/L vs.control group,0.63±0.07 g/L,P=0.021,BUN,observation group,16.95±1.54 mmol/1 vs.control group,6.92±0.67 mmol/l,P=0.000,CR,observation group,313.82±32.43 ? mol/1 vs.control group,100.97±10.43 ? mol/l,P=0.000,mortality,observation group,13(24.5)vs.control group,6(12.0),P=0.003,MDA,observation group,5.76±0.54 nmol/ml vs.control group,3.51±0.31 nmol/ml,P=0.028),while the HDL-C in the observation group was significantly lower than that in the control group(HDL-C,observation group,34.45±3.54 mg/dl vs.control group 52.23±4.99 mg/dl P=0.000).The differences were statistically significant.TG,ET-1 and TNF-? in group ? were significantly higher than those in group ?(TG,group ?,119.21±12.09 mg/dl vs.group ?,86.45±7.89 mg/dl,P=0.027,ET-1,group ?,121.54±11.54 pg/ml vs.group ?,105.63±11.45 pg/ml,P=0.019,TNF-a,group ?,1.12±0.12g/L vs.group ?,0.59±0.05 g/L,P=0.032),and HDL-C was significantly lower than those in group ?(HDL-C,group ?,35.02±3.54 mg/dl vs.group ?,52.43±5.32 mg/dl,P=0.025).APACHE II score was positively correlated with TG,TNF-a,ET-1(r=0.8960,P=0.001;r=0.8563,P=0.001;r=8899,P=0.001),and negatively correlated with HDL-C(r=-0.9292,P=0.000).Conclusion1.Oxidative stress might play an important role in the pathogenesis of SRMD,and affects mucosa permeability.The degree of oxidative stress can be reflected by APACHE ? score,serum MDA and serum IMA.During this process,altered NO level may play a dual role,and NO that plays a pathological role may be induced by iNOS.2.The expression of TGF?1 in gastric mucosa of SRMD patients decreased with the aggravation of mucosal injury,which might be related to the decrease of TGF?1 synthesis in the disease state and the excessive consumption in the process of mucosal healing.The expression of IL1? in the gastric mucosa of patients with SRMD was elevated,and this change may promote oxidative stress and mast cell activation.3.CRP may be an indicator for assessing the degree of gastric mucosal damage for patients with SRMD.4.Acute cerebral hemorrhage patients with stress ulcer bleeding will cause systemic inflammatory response,and patients' blood lipid levels will change.The more serious the disease is,the lower the HDL-C will be and the higher the TG level will be,and the severity of the disease is related to the inflammatory response. |
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