2. Academic Validation
  3. Inhibition of aquaporin-9 ameliorates severe acute pancreatitis and associated lung injury by NLRP3 and Nrf2/HO-1 pathways

Inhibition of aquaporin-9 ameliorates severe acute pancreatitis and associated lung injury by NLRP3 and Nrf2/HO-1 pathways

  • Int Immunopharmacol. 2024 Aug 20:137:112450. doi: 10.1016/j.intimp.2024.112450.
Jiawei Chen 1,  Xiandong Zhu 2,  Ziqiong Wang 1,  Michael Rützler 3,  Qiaohong Lu 1,  Hongjie Xu 1,  Roland Andersson 4,  Yinwei Dai 1,  Zouwen Shen 1,  Giuseppe Calamita 5,  Shangjing Xie 6,  Yongheng Bai 7,  Bicheng Chen 8
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China.
  • 2 Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province, China.
  • 3 ApoGlyx AB, Lund, Sweden, & Department of Biochemistry and Structural Biology, Lund University, Lund, Sweden.
  • 4 Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.
  • 5 Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari, Italy.
  • 6 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: a88310117@sina.com.
  • 7 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: wzbyh@wmu.edu.cn.
  • 8 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: bichengchen@hotmail.com.
PMID: 38906007 DOI: 10.1016/j.intimp.2024.112450
Abstract

Inflammation, Apoptosis and oxidative stress play crucial roles in the deterioration of severe acute pancreatitis-associated acute respiratory distress syndrome (SAP-ARDS). Unfortunately, despite a high mortality rate of 45 %[1], there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies[2]. This study investigated the potential therapeutic role and mechanisms of AQP9 inhibitor RG100204 in two animal models of severe acute pancreatitis, inducing acute respiratory distress syndrome: 1) a sodium-taurocholate induced rat model, and 2) and Cerulein and lipopolysaccharide induced mouse model. RG100204 treatment led to a profound reduction in inflammatory cytokine expression in pancreatic, and lung tissue, in both models. In addition, infiltration of CD68 + and CD11b + cells into these tissues were reduced in RG100204 treated SAP Animals, and edema and SAP associated tissue damage were improved. Moreover, we demonstrate that RG100204 reduced Apoptosis in the lungs of rat SAP Animals, and reduces NF-κB signaling, NLRP3, expression, while profoundly increasing the Nrf2-dependent anti oxidative stress response. We conclude that AQP9 inhibition is a promising strategy for the treatment of pancreatitis and its systemic complications, such as ARDS.

Keywords

Acute pancreatitis；AQP9, ARDS; Nrf2; Oxidative stress.

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