Uloga galektina 3 u eksperimentalnom modelu akutnog pankreatitisa
The role of galectin-3 in experimental acute pancreatitis
Author
Stojanović, BojanMentor
Lukić, Miodrag L.Committee members
Jovanović, IvanVojvodić, Danilo
Cvetković, Aleksandar
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Uvod: Akutni pankreatitis se karakteriše autodigestijom panckreasnih ćelija što je potom praćeno akutnom inflamacijom koja doprinosi razvoju patoloških promena i smrtnom ishodu. U eksperimentalnim uslovima je pokazano da galektin 3 eksprimiraju acinusne ćelije i infiltrišući makrofagi, ali je nepoznata uloga ovog lektina u
razvoju akutnog pankreatitisa.
Materijal i metode: Akutni pankreatitis je uzrokovan podvezivanjem biliopankreatinog duktusa ili sekvencijalnom i intraperitonealnom primenom ceruleina i
lipopolisaharida kod miševa divljeg soja i miševa sa delecijom gena za galektin 3.
Rezultati: Delecija galektina 3 je poboljšala preživljavanje miševa usled smanjenja
težine inflamacije pankreasa što je praćeno redukovanim leukocitnim infiltratom,
nižim vrednostima amilaza u serumu i aktivnošću tripsina u pankreasu, smanjenom
infiltracijom makrofaga i neutrofila koji eksprimiraju TLR-4, a posebno proinflamacijskih neutrofila. Galektin 3 i TLR-4 su kolokalizovani na površini
leu...kocita u infiltratu. Primena inhibitora TLR-4, CLI-095, poboljšala je
preživljavanje obolelih miševa. Nedostatak galektina 3 je praćen manjom produkcijom
TNF-α i IL-1β iz makrofaga i dendritskih ćelija. Delecija gena za galetin 3 je praćena i
manjom produkcijom IFN-γ iz T limfocita, NK i NKT ćelija, manja je aktivacija IL-
23/IL-17 osovine i povećana je infiltracija regulatornih T limfocita koji produkuju
IL-10 u pankreasu izolovanog iz obolelih miševa.
Zaključak: Delecija galektina 3 smanjuje težinu akutnog pankreatitisa u dva
eksperimentalna modela bolesti uticajem na influks neutrofila i mononuklearnih
ćelija urođene i stečene imunosti. Ove injenice ukazuju da primena inhibitora
galektina 3 može imati povoljan efekat na progresiju akutnog pankreatitisa.
Introduction: Acute pancreatitis is characterized by autodigestion of pancreatic cells followed by acute inflammation leading to pathology and death. In experimental acute pancreatitis, pancreatic acinar cells and infiltrating macrophages express Galectin-3 but its role in pathology is unknown.
Material and methods: Acute pancreatitis was induced by ligation of bile-pancreatic duct or sequential peritoneal administration of cerulein and lipopolysaccharide to wild-type and
Galectin-3 deficient C57BL/6 mice. We determined survival of mice, serum concentrations of
amylase, pancreatic pathology, and phenotypic and molecular features of inflammatory cells.
Therefore, we studied its role using Galectin-3 deficient mice.
Results: Deletion of Galectin-3 prolonged survival of mice contributed to attenuation of
histopathology, reduced leukocytes infiltration, lowered serum amylase concentration and
pancreatic trypsin activity, and decreased infiltration of macrophages and neutrophils that...
express TLR-4, in particular, pro-inflammatory N1 neutrophils. Galectin-3 and TLR-4 are
also colocalized on infiltrating cells. Additionally, administration of CLI-095, the specific
inhibitor of TLR-4, prolonged survival of diseased animals. Furthermore, lack of Galectin-3
reduced expression of pro-inflammatory TNF-α and IL-1β in F4/80+CD11c- macrophages and
CD11c+F4/80- dendritic cells. Gal-3 deficiency decreased the total number of IFN-γ-
producing CD3+CD49- T cells, CD3-CD49+ NK cells, and CD3+CD49+ NKT cells;
downregulated activation of IL-23/IL-17 axis and increased accumulation of IL-10-producing
Foxp3+ T regulatory cells in pancreata of diseased animals.
Conclusion: Deletion of Galectin-3 ameliorates acute pancreatitis in the two experimental
models by attenuating early influx of neutrophils and inflammatory mononuclear cells of
innate and acquired immunity. These findings provide the basis to consider Galectin-3 as a
therapeutic target in acute pancreatitis.