背景:败血症患者存在急性胃肠道损伤(AGI)的高风险,但脓毒症引起的AGI的诊断和治疗并不令人满意。乙酰肝素酶(HPA)在脓毒症AGI(S-AGI)中起重要作用,但是它的具体机制还不完全清楚,很少有临床报告。
目的:探讨抑制HPA对S-AGI患者的作用及机制。
方法:在我们的前瞻性临床试验中,将48例S-AGI患者随机分为对照组,接受常规治疗,47例患者被随机分配到干预组,接受常规治疗联合低分子肝素。AGI等级,序贯器官衰竭评估评分,急性生理和慢性健康评估II评分,D-二聚体,活化部分凝血活酶时间(APTT),抗Xa因子,白细胞介素-6,肿瘤坏死因子-α,HPA,syndecan-1(SDC-1),LC3B(自噬标记),肠脂肪酸结合蛋白,D-乳酸,胃动素,胃泌素,CD4/CD8,重症监护病房(ICU)住院时间,1日住院时间和28天生存时间,治疗后第3天和第7天进行比较。比较了HPA和AGI分级以及LC3B之间的相关性。建立受试者工作特征(ROC)曲线评价HPA的诊断价值,S-AGI中的肠道脂肪酸结合蛋白和D-乳酸。
结果:干预组血清HPA和SCD-1水平较对照组明显降低(P<0.05)。此外,肠道脂肪酸结合蛋白,D-乳酸,AGI等级,胃动素,干预组胃泌素水平和序贯器官功能衰竭评估评分明显下降(P<0.05)。然而,LC3B,APTT,抗Xa因子,干预组CD4/CD8明显升高(P<0.05)。白细胞介素-6,肿瘤坏死因子-α,D-二聚体,急性生理和慢性健康评估II评分,ICU住院时间,住院时间,两组均有28d生存率(P>0.05)。相关分析显示HPA与LC3B之间呈显著负相关,HPA与AGI等级之间呈显著正相关。ROC曲线分析显示HPA对S-AGI诊断具有较高的特异性和敏感性。
结论:HPA作为S-AGI的诊断标志物具有巨大潜力。抑制HPA活性可减少SDC-1脱落并缓解S-AGI症状。HPA在胃肠道保护中的抑制作用可能通过增强自噬来实现。
BACKGROUND: Patients with sepsis are at high risk for acute gastrointestinal injury (AGI), but the diagnosis and treatment of AGI due to sepsis are unsatisfactory. Heparanase (HPA) plays an important role in septic AGI (S-AGI), but its specific mechanism is not completely understood, and few clinical reports are available.
OBJECTIVE: To explore the effect and mechanism of HPA inhibition in S-AGI patients.
METHODS: In our prospective clinical trial, 48 patients with S-AGI were randomly assigned to a control group to receive conventional treatment, whereas 47 patients were randomly assigned to an intervention group to receive conventional treatment combined with low molecular weight heparin. AGI grade, sequential organ failure assessment score, acute physiology and chronic health evaluation II score, D-dimer, activated partial thromboplastin time (APTT), anti-Xa factor, interleukin-6, tumour necrosis factor-α, HPA, syndecan-1 (SDC-1), LC3B (autophagy marker), intestinal fatty acid binding protein, D-lactate,
motilin, gastrin, CD4/CD8, length of intensive care unit (ICU) stay, length of hospital stay and 28-d survival on the 1st, 3rd and 7th d after treatment were compared. Correlations between HPA and AGI grading as well as LC3B were compared. Receiver operator characteristic (ROC) curves were generated to evaluate the diagnostic value of HPA, intestinal fatty acid binding protein and D-lactate in S-AGI.
RESULTS: Serum HPA and SCD-1 levels were significantly reduced in the intervention group compared with the control group (P < 0.05). In addition, intestinal fatty acid-binding protein, D-lactate, AGI grade,
motilin, and gastrin levels and sequential organ failure assessment score were significantly decreased (P < 0.05) in the intervention group. However, LC3B, APTT, anti-Xa factor, and CD4/CD8 were significantly increased (P < 0.05) in the intervention group. No significant differences in interleukin-6, tumour necrosis factor-α, d-dimer, acute physiology and chronic health evaluation II score, length of ICU stay, length of hospital stay, or 28-d survival were noted between the two groups (P > 0.05). Correlation analysis revealed a significant negative correlation between HPA and LC3B and a significant positive correlation between HPA and AGI grade. ROC curve analysis showed that HPA had higher specificity and sensitivity in diagnosis of S-AGI.
CONCLUSIONS: HPA has great potential as a diagnostic marker for S-AGI. Inhibition of HPA activity reduces SDC-1 shedding and alleviates S-AGI symptoms. The inhibitory effect of HPA in gastrointestinal protection may be achieved by enhanced autophagy.