Qingdao Medical College, Qingdao University, Qingdao, Shandong, China; Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong, China.
Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong, China.
Int Immunopharmacol. 2024 Jan 5;126:111301. doi: 10.1016/j.intimp.2023.111301. Epub 2023 Nov 27.
Intestinal barrier dysfunction frequently occurs as a complication in cases of severe acute pancreatitis (SAP); however, no effective therapeutic methods are available because the precise mechanism remains obscure. Recent research has elucidated the role of circulating exosomes in the progression of SAP. Therefore, the present study explored whether inhibiting circulating exosomes release would improve intestinal barrier injury triggered via SAP and investigated the possible underlying mechanism. In vivo, we found that circulating exosomes release exhibited a considerable increase in SAP rats than in SO rats, and GW4869, a suppressor of exosomes release, significantly decreased exosomes release in SAP rats. We also observed that GW4869 suppressed NLRP3 inflammasome-mediated pyroptosis within the intestine and alleviated intestinal barrier injury within SAP. Moreover, the inflammatory response and remote organ (kidney and lung) injury associated with SAP improved after GW4869 treatment. In vitro, we confirmed that depletion of exosomes with GW4869 could partially abolish the destructive effects of SAP rat plasma on the viability and barrier function of IEC-6 cells. In summary, our findings show that the suppression of the release of circulating exosomes effectively inhibits the process of pyroptosis mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome and, therefore, mitigates intestinal barrier dysfunction in SAP, suggesting that circulating exosomes may be a potential target for treating SAP.
肠屏障功能障碍常作为重症急性胰腺炎（SAP）的并发症发生；然而，由于其确切机制尚不清楚，因此尚无有效的治疗方法。最近的研究阐明了循环外泌体在 SAP 进展中的作用。因此，本研究探讨了抑制循环外泌体释放是否会改善 SAP 引发的肠屏障损伤，并研究了可能的潜在机制。在体内，我们发现 SAP 大鼠的循环外泌体释放明显增加，而外泌体释放抑制剂 GW4869 可显著减少 SAP 大鼠的外泌体释放。我们还观察到 GW4869 抑制了 NLRP3 炎性小体介导的肠内细胞焦亡，并减轻了 SAP 中的肠屏障损伤。此外，GW4869 治疗后 SAP 相关的炎症反应和远处器官（肾脏和肺）损伤得到改善。在体外，我们证实用 GW4869 耗尽外泌体可部分消除 SAP 大鼠血浆对 IEC-6 细胞活力和屏障功能的破坏作用。总之，我们的研究结果表明，抑制循环外泌体的释放可有效抑制 NOD 样受体蛋白 3（NLRP3）炎性小体介导的细胞焦亡过程，从而减轻 SAP 中的肠屏障功能障碍，提示循环外泌体可能是治疗 SAP 的潜在靶点。
