NETs在急性胰腺炎中调控vWF/ADAMTS13的机制及其对胰腺坏死进展的影响

急性胰腺炎（AP）早期胰腺局部存在广泛微血栓形成，参与胰腺坏死演进。我们的前期研究显示：1）促血栓因子vWF及其裂解蛋白ADAMTS13参与了这一过程，主要表现为vWF活性的增加和ADAMTS13的浓度和活性下降；2）病情较重的患者ADAMTS13活性下调程度超过浓度，提示除了消耗外，还存在ADAMTS13“活性抑制”现象。研究发现，血栓性疾病中中性粒细胞外陷阱网（NETs）的生成增加可导致ADAMTS13活性受损，而其机制与肽酰基精氨酸脱亚氨酶4 (PAD4)有关。因此本研究假设：NETs在AP早期随炎症释放，可通过PAD4影响ADAMTS13的活性，导致vWF活性增强，参与胰腺局部微血栓形成。我们拟通过临床观察研究和体内体外试验，利用PAD4KO和ADAMTS13KO等基因修饰动物，验证NETs在AP中调控vWF/ADAMTS13的机制及其影响，为临床治疗提供新的靶点。

Formation of microthrombi is a common finding in acute pancreatitis and involved in the evolution of pancreatic necrosis. Our previous studies showed:1)vWF, which is a prothrombatic factor and its cleaving protein ADAMTS13 participate in the evolution of pancreatic necrosis; 2) In patients with severe AP, the drop of ADAMTS13 concentration and activity are not on a pro rata basis suggesting impaired activity of ADAMTS13. According to previous studies in the literature, the formation of neutrophil extracellular traps(NETs) in thrombotic diseases was associated with reduced activity of ADAMTS13 and the PAD4 pathway was thought to be the underlying mechanism. Therefore, we hypothesized that: the formation of NETs was elevated with inflammatory response in the early phase of AP resulting in impaired activity of ADAMTS13 and increased activity of vWF through the PAD4 pathway, which contributes to the formation of microthrombi in the pancreatic microcirculation and consequent pancreatic necorsis. In this proposal, we aimed to test this hypothesis with clinical observational study combined with both in vitro and in vivo experiments. Genetically modified animals like PAD4KO and ADAMTS13KO mice will be used to explore the mechanism. The results of this study may offer a novel therapeutic tharget for treatment of AP in the future.