| Aims Non-steroidal anti-inflammatory drugs(NSAIDs)are commonly used as the population ages,but the incidence of small intestinal damage is as high as 70%.Small intestinal damage caused by NSAIDs is more common than upper digestive tract damage,and its diagnosis is difficult and there is no effective treatment.This study intends to retrospectively analyze the clinical features of NSAIDs-induced small intestinal damage,and explore the prevention and treatment effects and mechanisms of sofalcone and lafutidine on NSAIDs-induced small intestinal damage in vivo and in vitro.MethodsPart oneA retrospective analysis of the clinical medical records and endoscopy data of 446 inpatients who underwent capsule endoscopy(CE)at the Digestive Endoscopy Center of our hospital from July 2014 to July 2020.According to whether they took NSAIDs,patients were divided into NSAIDs group and control one.The clinical information and the final endoscopic diagnosis results of the two groups were compared,and the clinical features of NSAIDs-induced small bowel damage were analyzed.Part two(1)Eighteen SD rats were randomly divided into three groups: normal control group(Control group),indomethacin model group(IND group)and sofalcone intervention group(SFC group).Sofalcone was gavaged for 10 consecutive days,and indomethacin was gavaged on the last 5 days.The changes in body weight and food intake of rats were monitored,and the hemogram and serum biochemical levels were detected.The small intestinal mucosal tissues and contents were collected for transcriptome sequencing and 16 S r RNA flora detection.The lesions of the small intestinal mucosa,the degree of inflammation,the apoptosis of intestinal epithelial cells,the level of oxidative stress and the intestinal barrier function were evaluated.(2)The protective effect of sofalcone was evaluated by detecting Caco-2 cell viability and oxidative stress level.After the cells were treated with sofalcone,the activation of the p62/Keap1/Nrf2/HO-1 pathway was detected.In addition,the m RNA level of M1 typed polarization markers for macrophages was detected.Part three(1)Eighteen SD rats were randomly divided into three groups: normal control group(Control group),indomethacin model group(IND group)and lafutidine intervention group(LAF group).Lafutidine was gavaged for 10 consecutive days,and indomethacin was gavaged for the last 5 days.The changes of body weight and food intake were monitored,and the hemogram and serum biochemical levels were detected.Small intestinal mucosal tissues and contents were collected for transcriptome sequencing and flora detection.The damage,inflammation and intestinal barrier function of small intestinal mucosa were assessed.(2)By detecting the viability of Caco-2 cells,the protective effect of lafutidine on cells was evaluated.In addition,the anti-inflammatory effect of lafutidine was assessed by detecting the m RNA levels of inflammatory cytokines in macrophages.ResultsPart oneCompared with the control group,patients in the NSAIDs group were older,had a higher rate of CE due to gastrointestinal bleeding,and had lower levels of hemoglobin and serum albumin.The final CE diagnosis showed that the proportion of non-specific mucosal lesions(erythema,erosion,ulcer and stenosis)in the NSAIDs group was 48.0%,which was significantly higher than that of the control group,while the proportion of Crohn’s disease was significantly lower than that of the control group.The internal comparison results of the NSAIDs group showed that age was a risk factor for NSAIDs-induced small intestinal damage.In addition,a comparative analysis of NSAIDs-induced small intestinal damage showed that ulcers mainly occurred in the ileum,while erosion/erythema mainly occurred in the jejunum.After discontinuation of NSAIDs or taking other drugs(mucosal protectant,probiotics or antibiotics)in 13 patients with small intestinal injury,the CE reexamination showed significant improvement in the lesions.Part two(1)Indomethacin caused obvious small intestinal damage,mainly manifested as decreased food intake,weight loss,decreased hemogram and serum biochemical levels,shortened small intestine length,and increased small intestinal mucosal injury scores.After the intervention of sofalcone,the above indicators significantly improved.Transcriptome sequencing results suggested that sofalcone may have anti-inflammatory,inhibiting apoptosis and antioxidant effects.Further research found that the intervention of sofalcone significantly improved the inflammation of the small intestinal mucosa,the apoptosis of intestinal epithelial cells,the level of oxidative stress and the intestinal barrier function.In addition,sofalcone improved the imbalance of intestinal flora induced by indomethacin and increased the abundance of lactobacillus.(2)The result of cell experiment showed that comparing with the IND group,the pretreatment with sofalcone significantly increased the viability of Caco-2 cells and inhibited the level of oxidative stress.The study of underlying mechanism found that the Nrf2/HO-1 pathway was obviously activated after treatment with sofalcone.Further studies have found that sofalcone can activate the upstream signaling pathway p62/Keap1 of Nrf2,and had nothing to do with autophagy dysfunction.In addition,sofalcone can reduce the expression of i NOS,CXCL10 and MCP-1 m RNA induced by LPS in macrophages,and inhibit M1 type polarization of macrophages.Part three(1)Comparing with the IND group,rats in the LAF group had significant improvements in food intake and weight,hemogram and serum biochemical levels,small intestinal length,and small intestinal mucosal injury scores.Transcriptome sequencing results suggested that lafutidine may have positive effects on inflammation,intestinal mucosal barrier and the repair of intestinal epithelial damage.Further research found that the degree of small intestinal mucosal inflammation and intestinal barrier function in the LAF group were significantly improved comparing with that in the IND group.In addition,the abundance of Lactobacillus acidophilus increased significantly in the LAF group.(2)The results of in vitro cell experiments showed that lafutidine had no protective effect on Caco-2 cell injury induced by indomethacin,and it had no effect on the expression of macrophage inflammatory factors induced by LPS.ConclusionsNSAIDs-induced small intestinal damage has a high incidence,and the age is a risk factor.It is mainly manifested as non-specific mucosal lesions under CE.Therefore,CE has a good diagnosis and guiding treatment effect on NSAIDs-induced small intestinal damage.Sofalcone can significantly improve the indomethacin-induced small intestinal damage in rats,which may be mainly through enhancing ability to resist oxidative stress by the activation of p62/Keap1/Nrf2/HO-1 pathway,inhibiting inflammation,enhancing the intestinal barrier function and regulating the intestinal flora.Lafutidine can also notably improve indomethacin-induced small intestinal damage in rats by enhancing the intestinal mucosal barrier,inhibiting inflammation,and regulating flora,but it has no protection in vitro. |
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