UEG Journal Abstracts 2023 - 83

Notably, these results remain significant after factoring in 74 potential
confounding variables such as alcohol consumption, smoking status, and
antibiotics. No differences were observed in alpha-diversity. Classifier for
severity was built with different abundant taxa achieving an AUROC of
80%.
Conclusion: The rectal but not oral microbiome has the ability to predict
the course of acute pancreatitis at admission of the patient.
Disclosure: Nothing to disclose.
OP085
NANO HYDROGEN AMELIORATES SEVERE ACUTE PANCREATITIS
X. Zeng1,2
, X. Yuan3, C. Zhao1,3
1
, J. Gao1,3
, C. Tang1,3
West China Hospital, Sichuan University, Lab of Gastroenterology
and Hepatology, Chengdu, China, 2
West China School of Public
Health and West China Fourth Hospital, Sichuan University,
Department of Gastroenterology, Chengdu, China, 3
OP084
MECHANISMS OF CRAC-NFATC1 SIGNALING IN THE PATHOGENESIS
OF ACUTE PANCREATITIS
A. Weber1, M.U. Latif1
1
, C.S. Gibhardt2
, I. Bogeski2
, V. Ellenrieder1
Universitätsmedizin Göttingen, Gastroenterologie, GI Onkologie
und Endokrinologie, Goettingen, Germany, 2
Universitätsmedizin
Göttingen, Herz- und Kreislaufphysiologie, Goettingen, Germany
Contact E-Mail Address: annalena.weber@med.uni-goettingen.de
Introduction: The mortality rate of severe acute pancreatitis is still high
and no causative treatment is currently available. Growing evidence suggest
a critical role of CRAC channel activation, disruption of Calcium homeostasis
and unresolved chronic ER stress in the pathogenesis of the
disease. In addition, recent clinical trials are currently analyzing the therapeutic
potential of specific CRAC channel inhibitors in patients with acute
pancreatitis.
Aims & Methods: Here, we studied the role and impact of the calcium responsive
Nuclear Factor of Activated T-Cells 1 (NFATc1) in CRAC channel
mediated signaling and inflammation during the course of acute pancreatitis.
We
employ Caerulein-induced in-vivo and in-vitro pancreatitis models,
using genetically modified mice with differential activation of NFATc1
and freshly isolated primary acinar cells. For functional characterization,
Western-Blot, qPCR and Immunofluorescence microscopy have been conducted.
Currently whole proteome Mass-Spectrometry based approaches,
as well as RNA Sequencing are being established to gain understanding of
global transcriptional and translational changes.
Results: We show that Caerulein induced rapid NFATc1 expression, nuclear
translocation and activation in pancreatic tissues, primary acinar cells
and in cultured acinar cells. NFATc1 induction is associated with upregulation
of ER-stress related proteins, altered intracellular calcium signaling
and induction of key inflammatory cytokines.
Moreover, inhibition of NFATc1 - either genetically or following application
of CRAC channel inhibitors (CM4620/Auxora) significantly reduces
expression and release of pro-inflammatory cytokines in primary acinar
cells. In addition, genetic inactivation of NFATc1 reduces the severity of
acute pancreatitis and prevents immune cell infiltration in mice.
The therapeutic potential of CM4620 mediated CRAC channel/NFATc1
signaling inhibition in acute pancreatitis prevention and treatment is currently
under investigation.
Conclusion: We propose that CRAC channel - NFATc1 signaling promotes
inflammation and tissue damage in acute pancreatitis through regulation
of cell-stress responses, cytokine release and immune cell infiltration.
Moreover, pharmacological inactivation of the CRAC-NFATc1 pathway
might offer novel therapeutic option in treatment of severe acute pancreatitis.
Disclosure:
Nothing to disclose.
West China
Hospital, Sichuan University, Department of Gastroenterology and
Hepatology, Chengdu, China
Contact E-Mail Address: ruading@163.com
Introduction: During severe acute pancreatitis (SAP), large amounts of reactive
oxygen species (ROS) are produced in the abdominal cavity, which
can directly damage abdominal organs and be absorbed into the blood,
causing systemic inflammatory response syndrome and multiple organ
dysfunction. Molecular hydrogen (H2
such as hydroxyl radical [1]
) can target to eliminate harmful ROS
.
When severe inflammatory damage occurs in the pancreas, microthrombosis
are widely produced, and the antioxidant effect is difficult to be fully
exerted if H2
is administered through circulation.
Aims & Methods: We have developed hydrogen-loaded nanoparticles
(nano hydrogen) to bring H2
into direct contact with the pancreas by intraperitoneal
administration, providing a new strategy for the anti-inflammatory
treatment of SAP. In this study, we investigated the pathophysiological
mechanisms by which nano hydrogen ameliorates SAP.
In vivo, SAP was established by retrograde injection of sodium taurocholate
through the rat pancreatic duct. Nano hydrogen (37.5 mg/kg) was injected
intraperitoneally in the SAP + nano hydrogen group. The survival
rate was calculated.
Pathological scoring was performed. Neutrophil and macrophage infiltration,
ultrastructural changes of acinar cells and vascular endothelial cells,
and microthrombosis of pancreatic tissue were detected. In vitro, intracellular
ROS of AR42J cells were measured using hydroxyphenyl fluorescein
solution. Human umbilical vein endothelial cells (HUVECs) were stimulated
with TNF-α, and nano hydrogen was used for intervention. RNA-seq
was performed on rat pancreatic tissue and HUVEC samples.
The expression of VCAM-1, ICAM-1 and NF-κB p65 in HUVECs was compared.
β-galactosidase staining and markers of cellular senescence such
as phosphorylated γ-H2
A.X, p53, p21, and p16 were detected. The opening
of the mitochondrial permeability transition pore (MPTP) and mitochondrial
membrane potential of HUVECs were assessed.
Results: After intraperitoneal administration of nano hydrogen into SAP
rats, the survival rate increased by 66%, and the pathological score of pancreas
dramatically decreased (p < 0.01). The neutrophil infiltration was
significantly reduced (p < 0.01), and the ultrastructure of acinar cells and
vascular endothelial cells was significantly improved. The pancreatic tissue
of SAP rats had a large number of microthrombi, which were significantly
reduced by nano hydrogen. Pancreatic vascular endothelial cells in
SAP rats expressed p21.
Nano hydrogen significantly downregulated the dominant transcriptional
events in SAP pancreas, such as leukocyte chemotaxis and migration and
oxidative stress, and also significantly reduced the production of ROS in
the acinar cells and the expression of VCAM-1, ICAM-1 and phosphorylated
p65 after TNF-α stimulation of HUVECs (p < 0.01).
RNA-seq analysis of HUVECs indicated that TNF-α induced cellular senescence,
confirmed by positive β-galactosidase staining and significantly increased
expression of phosphorylated γ-H2
A.X, total p53, phosphorylated
p53, p21 (p < 0.05) and p16 (p < 0.01).
MPTP opened and mitochondrial membrane potential disappeared in
TNF-α-stimulated HUVECs. Nano hydrogen significantly attenuated the
abovementioned manifestation.
Vol. 11 | October 2023
83
Tuesday, October 17, 2023
Monday, October 16, 2023
Sunday, October 15, 2023
UEG Journal Abstracts 2023

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