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

Autor: Liu M; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Department of Gastroenterology, NO. 905 Hospital of PLA Navy affiliated to Naval Medical University, Shanghai, 200050, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Ma L; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China; Department of Gastroenterology, No 988 Hospital of PLA Joint Logistics Support Force, Zhengzhou, 450000, China., An W; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Yang Y; Department of Pathology, Molecular Medicine and Cancer Research Center, Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, China., Liu J; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Jiang H; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China; Department of Pathology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China., Yuan J; Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China., Sun X; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Zhu J; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Yan M; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Wang L; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Li Z; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Liao Z; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China. Electronic address: liaozhuan@smmu.edu.cn., Sun C; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China. Electronic address: sunchang8211@163.com.
Jazyk: angličtina
Zdroj: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] [Pancreatology] 2024 Aug; Vol. 24 (5), pp. 677-689. Date of Electronic Publication: 2024 May 07.
DOI: 10.1016/j.pan.2024.05.514
Abstrakt: 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.
(Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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