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

Chen, Jiawei ; Zhu, Xiandong ; Wang, Ziqiong ; Rützler, Michael LU ; Lu, Qiaohong ; Xu, Hongjie ; Andersson, Roland LU ; Dai, Yinwei ; Shen, Zouwen and Calamita, Giuseppe , et al. (2024) In International Immunopharmacology 137.
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Acute pancreatitis；AQP9, ARDS, Nrf2, Oxidative stress
in
International Immunopharmacology
volume
137
article number
112450
publisher
Elsevier
external identifiers
  • scopus:85196307322
  • pmid:38906007
ISSN
1567-5769
DOI
10.1016/j.intimp.2024.112450
language
English
LU publication?
yes
id
1fa33345-20e3-470b-b493-fafd76d6e2d2
date added to LUP
2024-07-03 10:54:32
date last changed
2024-07-17 14:10:17
@article{1fa33345-20e3-470b-b493-fafd76d6e2d2,
  abstract     = {{<p>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.</p>}},
  author       = {{Chen, Jiawei and Zhu, Xiandong and Wang, Ziqiong and Rützler, Michael and Lu, Qiaohong and Xu, Hongjie and Andersson, Roland and Dai, Yinwei and Shen, Zouwen and Calamita, Giuseppe and Xie, Shangjing and Bai, Yongheng and Chen, Bicheng}},
  issn         = {{1567-5769}},
  keywords     = {{Acute pancreatitis；AQP9, ARDS; Nrf2; Oxidative stress}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{International Immunopharmacology}},
  title        = {{Inhibition of aquaporin-9 ameliorates severe acute pancreatitis and associated lung injury by NLRP3 and Nrf2/HO-1 pathways}},
  url          = {{http://dx.doi.org/10.1016/j.intimp.2024.112450}},
  doi          = {{10.1016/j.intimp.2024.112450}},
  volume       = {{137}},
  year         = {{2024}},
}