Heparanase Inhibitors Improve Patients With Acute Gastrointestinal Injury Induced By Sepsis

Aim: Acute gastrointestinal injury(AGI)is very likely to occur in patients with sepsis,but the diagnosis and treatment of septic AGI are not very satisfactory.Heparanase(HPA)plays an important role in septic AGI,but its specific mechanism is not fully understood,especially the clinical report is very rare.Therefore,we aimed to explore the effects of suppressed HPA levels on septic AGI patients and its mechanism.Methods: In our prospective clinical trial,165 patients with sepsis admitted to the department of intensive care medicine of the First Hospital of Lanzhou University from January 2021 to January 2022 were selected.After screening,a total of 95 patients with septic AGI were finally included and 48 patients with septic AGI were randomly assigned to the control group and given routine treatment,and 47 patients were randomly assigned to the intervention group to receive conventional treatment combined with low molecular weight heparin.Gastrointestinal functional indexes(AGI grading,intestinal fatty acid binding protein,D-lactate,motilin,gastrin),HPA-related indexes(HPA,syndecan-1),coagulation indexes(d-dimer,activated partial thromboplastin time,anti-Xa factor),inflammatory factors(interleukin-6,tumor necrosis factor-α),autophagy related indexes(LC3B),immune-related indicators(CD4/CD8),disease severity(SOFA score,APACHE Ⅱ score),length of ICU stay,total length of stay and 28-day survival rate were compared at day 1,3,and7 after intervention.The correlation between HPA and AGI grading and HPA and LC3 B was compared.ROC curve was used to evaluate the diagnostic value of HPA,intestinal fatty acid binding protein and D-lactate in septic AGI.Univariate and multivariate Logistic regression were used to analyze the risk factors for 28-day mortality in septic AGI patients.Results: Serum HPA and syndecan-1 levels in the intervention group were significantly reduced compared with the control group(P < 0.05),and the intestinal fatty acid binding protein,D-lactate,AGI grade,motilin,gastrin and SOFA scores in the intervention group were also significantly decreased(P < 0.05).LC3 B,activated partial thromboplastin time,anti-Xa factor and CD4/CD8 were significantly increased(P< 0.05).There were no significant differences in interleukin-6,tumor necrosis factor-α,d-dimer,APACHE Ⅱ score,length of ICU stay,total length of hospital stay and 28 d survival between the two groups(P > 0.05).Correlation analysis showed that there was a negative correlation between HPA and LC3 B,and a positive correlation between HPA and AGI grade.ROC curve showed that HPA had higher specificity and sensitivity in the diagnosis of septic AGI.Univariate analysis showed that body mass index,APACHE Ⅱ score,SOFA score,pulmonary infection,AGI Ⅳgrade and serum HPA level were risk factors affecting the 28-day mortality of patients,while multivariate analysis did not show statistical significance.Conclusion: Inhibition of HPA activity can effectively reduce the shedding of syndecan-1,help to maintain the integrity of intestinal epithelial cells and barrier function,and alleviate septic AGI symptoms.Inhibition of HPA may play a protective role in gastrointestinal tract by enhancing the level of autophagy.HPA is a biomarker of potential septic AGI.However,further large-scale,multicenter prospective clinical trials are needed to confirm our findings.