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

Tesis (Magíster en Biotecnología y Ciencias de la Vida) 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.