Effect of oral administration of the pharmacological inhibitor of type I TGF-β receptor, GW788388, on fibrosis, organ dysfunction, cardiovascular variables, and survival during endotoxemia
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Fecha
2019
Profesor/a Guía
Facultad/escuela
Idioma
es
Título de la revista
ISSN de la revista
Título del volumen
Editor
Universidad Andrés Bello
Nombre de Curso
Licencia CC
Licencia CC
Resumen
Sepsis syndrome is the leading cause of mortality in critically ill patients admitted to
intensive care. However, current therapies for sepsis treatment are unsatisfactory, and the
mortality rate is still high. The main pathological characteristics observed during sepsis
syndrome and endotoxemia include hypotension, tachycardia, MODS, tissue damage, and
cytokine and oxidative bursts. These conditions severely decrease the survival rates of
endotoxemic patients. As a consequence of endotoxemia, large amounts of endotoxin
circulate in the bloodstream throughout the vascular system and interact directly with
endothelial cells that cover the inner wall of blood vessels.
Endothelial cells exposed to lipopolysaccharides exhibit conversion to activated fibroblasts.
By means of endotoxin-induced endothelial fibrosis, endothelial cells downregulate the
expression of endothelial proteins and express fibrotic and ECM markers throughout
endothelial protein expression reprogramming. Despite that endotoxin-induced endothelial
fibrosis should be detrimental to endothelial vascular function, the contribution of
endothelial fibrosis during sepsis syndrome or endotoxemia is not known. Therefore, it is
investigated whether the inhibition of endotoxin-induced endothelial fibrosis protects against
endotoxemia via the main endotoxemia characteristics and whether this inhibition increases
survival. The working hypothesis is: Oral administration of the pharmacological inhibitor of
fibrosis GW788388 during endotoxemia inhibits fibrosis, pro-inflammatory cytokine
production, and oxidative burst, improving cardiovascular variables, MODS and survival
rate.
The results demonstrate that the inhibition of endotoxin-induced endothelial fibrosis
reduced both hypotension and tachycardia. Endotoxemia-induced MODS was also decreased
in the endothelial fibrosis-inhibited condition, showing normal kidney and liver function, inhibition of muscle mass wasting and normal glycaemia. Liver and kidney histology were
preserved, and organ fibrosis and fibrotic protein expression were reduced. Furthermore,
pro-inflammatory cytokine secretion and NOX2-mediated oxidative stress bursts were
decreased in the endothelial fibrosis-inhibited condition. Remarkably, the mortality
associated with sepsis syndrome at early and late time points was decreased when
endotoxemia-induced endothelial fibrosis was inhibited, showing a significant increase in
survival.
These results show a potential novel treatment strategy to protect against sepsis
syndrome and endotoxemia.
Notas
Tesis (Magíster en Biotecnología y Ciencias de la Vida)
Palabras clave
Sepsis, Tratamiento, Administración Oral, Inhibidores Farmacológicos