Heterozygous Spink1 c.194+2T>C mutation promotes chronic pancreatitis after acute attack in mice

作者全名："Liu, Muyun; Ma, Lizhe; An, Wei; Yang, Yaying; Liu, Juncen; Jiang, Hui; Yuan, Jihang; Sun, Xiaoru; Zhu, Jingyi; Yan, Maoyun; Wang, Luowei; Li, Zhaoshen; Liao, Zhuan; Sun, Chang"

作者地址："[Liu, Muyun; Ma, Lizhe; An, Wei; Liu, Juncen; Sun, Xiaoru; Zhu, Jingyi; Yan, Maoyun; Wang, Luowei; Li, Zhaoshen; Liao, Zhuan; Sun, Chang] Naval Med Univ, Affiliated Hosp 1, Dept Gastroenterol, Shanghai 200433, Peoples R China; [Liu, Muyun] Naval Med Univ, Dept Gastroenterol, Hosp PLA Navy 905, Shanghai 200050, Peoples R China; [Liu, Muyun; Ma, Lizhe; An, Wei; Liu, Juncen; Jiang, Hui; Sun, Xiaoru; Zhu, Jingyi; Yan, Maoyun; Wang, Luowei; Li, Zhaoshen; Liao, Zhuan; Sun, Chang] Shanghai Inst Pancreat Dis, Shanghai 200433, Peoples R China; [Ma, Lizhe] 988 Hosp PLA Joint Logist Support Force, Dept Gastroenterol, Zhengzhou 450000, Peoples R China; [Yang, Yaying] Chongqing Med Univ, Mol Med & Canc Res Ctr, Mol Med Diagnost & Testing Ctr, Dept Pathol, Chongqing 400016, Peoples R China; [Jiang, Hui] Naval Med Univ, Affiliated Hosp 1, Dept Pathol, Shanghai 200433, Peoples R China; [Yuan, Jihang] Naval Med Univ, Dept Med Genet, Shanghai 200433, Peoples R China"

通信作者："Liao, Z; Sun, C (通讯作者)，Naval Med Univ, Affiliated Hosp 1, Dept Gastroenterol, Shanghai 200433, Peoples R China.; Liao, Z; Sun, C (通讯作者)，Shanghai Inst Pancreat Dis, Shanghai 200433, Peoples R China."

来源：PANCREATOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001270173400001

JCR分区：Q2

影响因子：3.6

年份：2024

卷号：24

期号：5

开始页：677

结束页：689

文献类型：Article

关键词：Acute pancreatitis; Chronic pancreatitis; SPINK1; SAPE

摘要："Background & aims: Mutations in genes, including serine protease inhibitor Kazal-type 1 (SPINK1), influence disease progression following sentinel acute pancreatitis event (SAPE) attacks. SPINK1 c.194+2T > C intron mutation is one of the main mutants of SPINK1,which leads to the impairment of SPINK1 function by causing skipping of exon 3. Research on the pathogenesis of SAPE attacks would contribute to the understanding of the outcomes of acute pancreatitis. Therefore, the aim of the study was to clarify the role of SPINK1 c.194+2T > C mutation in the CP progression after an AP attack. Methods: SAPE attacks were induced in wildtype and SPINK mutant (Spink1 c.194+2T > C) mice by cerulein injection. The mice were sacrificed at 24 h, 14 d, 28 d, and 42 d post-SAPE. Data-independent acquisition (DIA) proteomic analysis was performed for the identification of differentially expressed protein in the pancreatic tissues. Functional analyses were performed using THP-1 and HPSCs. Results: Following SAPE attack, the Spink1 c.194+2T > C mutant mice exhibited a more severe acute pancreatitis phenotype within 24 h. In the chronic phase, the chronic pancreatitis phenotype was more severe in the Spink1 c.194+2T > C mutant mice after SAPE. Proteomic analysis revealed elevated IL-33 level in Spink1 c.194+2T > C mutant mice. Further in vitro analyses revealed that IL-33 induced M2 polarization of macrophages and activation of pancreatic stellate cells. Conclusion: Spink1 c.194+2T > C mutation plays an important role in the prognosis of patients following SAPE. Heterozygous Spink1 c.194+2T > C mutation promotes the development of chronic pancreatitis after an acute attack in mice through elevated IL-33 level and the induction of M2 polarization in coordination with pancreatic stellate cell activation. (c) 2024 IAP and EPC. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies."

基金机构："National Natural Science Foundation of China [82000609, 81970559, 82170658, 82270677]; First Affiliated Hospital of Naval Medical University 234 Discipline Peak Climbing Plan Clinical Discipline Innovation Project [2020YXK014]; Shanghai Rising Star of Medical Talents Youth Development Program (SHWSRS); Hospital of PLA Navy [905, 2021Q010]; Hospital of PLA Navy [905, 2023QN27]; Shanghai Changning District Health Commission Youth Project [2021Q010]; Shanghai Changning District Health Commission Youth Project; [62]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (no. 82000609 (to ML), 81970559 (to SC), 82170658 (to SC), 82270677 (to WA)); First Affiliated Hospital of Naval Medical University 234 Discipline Peak Climbing Plan Clinical Discipline Innovation Project (no.2020YXK014 (to SC)); Shanghai Rising Star of Medical Talents Youth Development Program (SHWSRS (2023) 62 (to ML); Scientific Research Project of NO. 905 Hospital of PLA Navy (no. 2021Q010 (to ML)); Shanghai Changning District Health Commission Youth Project (2023QN27 (to ML))."