Lim Seok Ting, Zhao Xinmei, Liu Shuqing, Zhang Wenjuan, Tan Yuanyang, Mullappilly Nidula, Swain Sandip M, Leong Mei Ling, Rajarethinam Ravisankar, Wan Kah Fei, Ruedl Christiane, Liddle Rodger A, Li Liang, Wang Xiaomeng
Centre for Vision Research, Duke-NUS Medical School, Singapore.
Singapore Eye Research Institute, Singapore.
Theranostics. 2025 Mar 18;15(10):4247-4269. doi: 10.7150/thno.110116. eCollection 2025.
Acute pancreatitis (AP) is a common gastrointestinal disease affecting nearly 3 million people annually worldwide. Although AP is typically self-limiting, up to 20% of patients may develop life-threatening complications. Individuals who suffer from AP also have an increased likelihood of developing other exocrine and endocrine pancreatic disorders. However, to date, there are no specific, targeted treatment modalities that can effectively improve the clinical outcomes of AP. Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a multifunctional protein with established roles in inflammation and cell mitosis. This study aims to investigate the functional role of LRG1 in AP progression and develop LRG1-targeted AP therapeutics. Levels of circulating and tissue LRG1 were determined in human patient samples and mouse models of caerulein-induced AP and pancreatic duct ligation-induced AP. Histopathological grading, amylase assay, real-time polymerase chain reaction analysis and Western blotting were used to evaluate the extent of pancreatic damage and recovery following caerulein-induced AP in both wild-type and mice. Primary acinar cells were also isolated from mice for in-vitro mechanistic studies. LRG1 neutralizing antibody was administered post-AP induction to evaluate its therapeutic potential in improving AP outcomes. LRG1 is markedly increased in serum and acinar cells of AP patients and C57BL/6 mice subjected to caerulein-induced AP or pancreatic duct ligation-induced AP. Despite demonstrating no obvious pancreatic dysfunction, mice exhibited more severe pancreatic damage and inflammation during the early stages of caerulein-induced AP. However, the resolution of AP was accelerated in the absence of Lrg1, which is at least partially due to LRG1's role in regulating the expression of trophic cholecystokinin (CCK) Type 1 receptor (CCK1R) via the TGFβ/ALK5/AKT pathway in acinar cells. Importantly, the administration of an LRG1-blocking antibody promoted AP recovery, evidenced by reduced overall inflammation and increased acinar cell proliferation. Our data provide compelling evidence for targeting LRG1 as a potential innovative therapy for promoting AP recovery.
急性胰腺炎（AP）是一种常见的胃肠道疾病，全球每年有近300万人受其影响。虽然AP通常具有自限性，但高达20%的患者可能会出现危及生命的并发症。患有AP的个体患其他胰腺外分泌和内分泌疾病的可能性也会增加。然而，迄今为止，尚无能够有效改善AP临床结局的特异性靶向治疗方法。富含亮氨酸的α-2糖蛋白1（LRG1）是一种多功能蛋白，在炎症和细胞有丝分裂中发挥着既定作用。本研究旨在探讨LRG1在AP进展中的功能作用，并开发针对LRG1的AP治疗方法。在人类患者样本以及雨蛙肽诱导的AP和胰管结扎诱导的AP小鼠模型中，测定了循环和组织中LRG1的水平。采用组织病理学分级、淀粉酶测定、实时聚合酶链反应分析和蛋白质免疫印迹法，评估野生型和 小鼠在雨蛙肽诱导的AP后胰腺损伤和恢复的程度。还从小鼠中分离出原代腺泡细胞用于体外机制研究。在AP诱导后给予LRG1中和抗体，以评估其改善AP结局的治疗潜力。在接受雨蛙肽诱导的AP或胰管结扎诱导的AP的AP患者和C57BL/6小鼠的血清和腺泡细胞中，LRG1显著增加。尽管 小鼠未表现出明显的胰腺功能障碍，但在雨蛙肽诱导的AP早期阶段，其胰腺损伤和炎症更为严重。然而，在缺乏Lrg1的情况下，AP的消退加速，这至少部分归因于LRG1通过腺泡细胞中的TGFβ/ALK5/AKT途径调节营养性胆囊收缩素（CCK）1型受体（CCK1R）表达的作用。重要的是，LRG1阻断抗体的给药促进了AP的恢复，表现为总体炎症减轻和腺泡细胞增殖增加。我们的数据为将LRG1作为促进AP恢复的潜在创新疗法提供了有力证据。
