超声造影介导PLA2 抑制剂治疗胰腺挫裂伤的机制研究

The incidence of pancreatic trauma is 0.4/100,000, and it only occupies 1%-3% in abdominal trauma. However, its mortality is highly to 70-80% when the severe complications such as large vessels break, intestinal fistula and infection of abdominal cavity occur. Sometimes the minimal pancreatic contusion can not be found even in laparotomy. The pancreatic juice enters pancreas parenchyma and its surroundings. And then pancreatic enayma is activated followed by pancreas itself and surroundings digesting, which will lead to second pancreatic rupture and surrounding tissues injuries. Therefore the mild traumatic pancreatic injury often causes the serious consequence accounting for a mortality of 20% because of low diagnosis accuracy and lack of effective treatment measures at early stage. Studies have demonstrated that it is a key step to activate phospholipase A2(PLA2) during the procedure of developing serious tramatic panreatitis from mild. The cascade amplification effect due to PLA2 will be stopped if downstream products of PLA2 are controlled. However, at present most studies focus on surgical remedy or system venous administration for pancreas lesion and trauma complications. It is severely deficient to study the mechanism of contrast enhanced ultrasound-mediated PLA2 inhibitor treating pancreatic contusions. In the previous series researches on abdominal parenchyma organ trauma, our team successfully makes contrast micro-bubbles and focal hemostatic agent, develops animal and patient experiments. These studies have demonstrated that abdominal parenchyma organ trauma can be diagnosed with contrast enhanced ultrasound up to an accuracy of 95-97%, can be effectively treated under the guidance of contrast enhanced ultrasound. Especially the preliminary researches on pancreas rupture in the animal models have present the important value of contrast enhanced ultrasound in diagnosis of pancreas rupture. By series of studies, our team has addressed 59 articles including 13 SCI, obtained 5 national patents and the first prize of the army technology progress. The applicant has been going in for these projects as a major researcher and postgraduate instructor. On the basis of it, we design this project including: ①Modeling animals with traumatic pancreatic injury of gradesⅠandⅡ. ②Contrast enhanced ultrasound will be performed for realizing early diagnosis of traumatic pancreas injury. ③Making a combined medicine with PLA2 inhibitor and focal hemostatic agent. ④Pancreatic lesion and its surroundings will be injected with the combined medicine under the guidance of contrast enhanced ultrasound for stopping PLA2 activity and bleeding. If these research ideas are realized successfully, traumatic pancreatic injury will be rapidly diagnosed and treated, and this technique also will be convenient for rescuing patient with pancreas trauma at pre-hospital and bedside.

胰腺挫裂伤（Ⅰ级和Ⅱ级创伤），即使术中难以发现的极小挫伤，含高浓度消化酶的胰液可由挫伤处溢至胰腺间质或胰周，随即被激活并对胰腺和胰周组织进行消化，导致"继发性断裂"、胰围大血管破裂等严重后果。在此过程中，磷脂酶A2（PLA2 ）激活是关键步骤，由PLA2诱发的级联放大效应可使轻型的Ⅰ和Ⅱ级胰腺挫裂伤演变成Ⅲ级以上的重症创伤性胰腺炎，死亡率达20％。若能阻止PLA2 下游产物的产生，可使PLA2 诱发的级联放大效应得以控制。本课题组在前期腹部实质器官创伤包括胰腺断裂伤的研究中，发表论文59篇，其中SCI论文15篇，获专利3项、军队科技进步一等奖1项，本项目申请人是其主要研究者，并担任研究生指导老师。基于上述，本项目拟构建联合PLA2 抑制剂与局部止血剂的新剂型，在超声造影引导下对胰腺挫裂伤部位及胰周直接给药，使其定点抑制PLA2 活性并止血，以阻止胰腺及其周围组织的"继发性消化"，促进愈合。

（一）胰腺挫裂伤的诊断：完成了闭合性胰腺挫裂伤的动物实验，胰腺挫裂伤的超声造影诊断。自行设计、制作了生物撞击器，使之具备如下特点：1.形成一个精确描述创伤形成机理的理论体系；2.同时高速获得多个描述创伤撞击过程的参数的撞击系统结构；3.撞击器的构型设计。完成了28例胰腺创伤的患者的超声造影诊断，明确了超声造影诊断胰腺创伤的准确率95.5%；明确了超声造影技术可方便地用于患者床旁，对那些存在严重合并伤难以搬动的患者价值更大。.（二）采用动物实验所采集的血液及液氮冻存胰腺标本进行了相关指标检测，包括胰腺挫裂伤的血清中PLA2 活性及表达时间及程度；并在超声造影引导行胰腺创伤灶及胰腺周围先后局部注射治疗医用吻合胶和胰酶抑制剂，使之在减轻胰液外漏的同时，减轻胰酶对周围组织的腐蚀，实现胰液外漏治疗。结果显示，超声引导微创治疗前后血清中PLA2 活性及程度显著不同，治疗后活性明显降低。.（三）进一步完成了胰腺挫裂伤早期局部药物治疗研究，明确了：（1）胰腺挫裂伤早期局部药物治疗中，乌司他丁可以有效抑制胰酶和自身消化作用，医用吻合胶可以有效保护创面，实现止血、封闭、粘合和堵漏效果，两者联合应用可以有效抑制血淀粉酶和脂肪酶的升高，有效减轻腹腔积液的积聚，改善预后，具有较好的治疗效果和较高的临床应用价值；（2）胰腺挫裂伤早期病程发展可能存在一段缓慢的平台期，该期可能成为胰腺挫裂伤早期干预的最佳治疗时间窗和病情评估及预后判断的观察窗；（3）胰腺挫裂伤的早期病程发展过程中，血脂肪酶较淀粉酶在评估病情发展程度方面更为敏感和准确，脂肪酶含量在6h～12h这个平台期内的变化情况可能作为胰腺挫裂伤预后和治疗效果的重要预测和评价指标。