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Cell-type specific role of phosphoinositide 3-kinase γ in inflammatory-induced cholestasis
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Mounting evidence indicates that the liver plays a key role in both the initiation and the promotion of MOF during sepsis. Among all liver functions, the hepatic formation and secretion of bile is critical to survival and is easily disrupted in septic conditions. Systemic inflammation negatively affects these delicate processes, leading to bile accumulation within hepatocytes (cholestasis), severely affecting liver functions and contributing to poor outcomes. Phosphoinositide-3 kinase y (PI3Ky) is recognized as a key contributor to inflammatory stress responses in both immune and non-immune cells. Previous studies showed that knockout mice for PI3Ky were protected from cholestasis in experimental mouse models of polymicrobial sepsis. However, the role of this kinase in liver parenchyma remains unknown. Initial investigations disclosed for the first time that liver parenchymal cells express PI3Ky. Most importantly, both WT primary hepatocytes and cell lines displayed increased PI3Ky expression upon exposure to a proinflammatory cytokine mix (CM), suggesting the involvement of this enzyme in inflammatory stress responses of liver parenchyma. Furthermore, we find that PI3Ky regulates the cellular localization of multidrug resistance-associated protein 2 (Mrp2), thus contributing to the pathogenesis of inflammatory-induced cholestasis. Furthermore, the lack of functional PI3Ky in primary hepatocytes increased the expression of heme oxygenase-1 (HO-1), which is known to exert hepatoprotective effects against inflammation-induced oxidative stress. Overall, our results point out a new cell-type specific role of PI3Ky in inflammatory-stress responses of liver parenchyma. Based on this study, hepatocyte-specific PI3Ky inhibition may represent a novel putative therapeutic strategy for preventing sepsis-induced cholestasis. ; Sepsis ist eine lebensbedrohliche, systemische Fehlreaktion des Körpers auf Infektionen. Zunehmende ...
Cell-type specific role of phosphoinositide 3-kinase γ in inflammatory-induced cholestasis
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Mounting evidence indicates that the liver plays a key role in both the initiation and the promotion of MOF during sepsis. Among all liver functions, the hepatic formation and secretion of bile is critical to survival and is easily disrupted in septic conditions. Systemic inflammation negatively affects these delicate processes, leading to bile accumulation within hepatocytes (cholestasis), severely affecting liver functions and contributing to poor outcomes. Phosphoinositide-3 kinase y (PI3Ky) is recognized as a key contributor to inflammatory stress responses in both immune and non-immune cells. Previous studies showed that knockout mice for PI3Ky were protected from cholestasis in experimental mouse models of polymicrobial sepsis. However, the role of this kinase in liver parenchyma remains unknown. Initial investigations disclosed for the first time that liver parenchymal cells express PI3Ky. Most importantly, both WT primary hepatocytes and cell lines displayed increased PI3Ky expression upon exposure to a proinflammatory cytokine mix (CM), suggesting the involvement of this enzyme in inflammatory stress responses of liver parenchyma. Furthermore, we find that PI3Ky regulates the cellular localization of multidrug resistance-associated protein 2 (Mrp2), thus contributing to the pathogenesis of inflammatory-induced cholestasis. Furthermore, the lack of functional PI3Ky in primary hepatocytes increased the expression of heme oxygenase-1 (HO-1), which is known to exert hepatoprotective effects against inflammation-induced oxidative stress. Overall, our results point out a new cell-type specific role of PI3Ky in inflammatory-stress responses of liver parenchyma. Based on this study, hepatocyte-specific PI3Ky inhibition may represent a novel putative therapeutic strategy for preventing sepsis-induced cholestasis. ; Sepsis ist eine lebensbedrohliche, systemische Fehlreaktion des Körpers auf Infektionen. Zunehmende ...
Cell-type specific role of phosphoinositide 3-kinase γ in inflammatory-induced cholestasis
Beretta, Martina (author) / Bauer, Michael / Wetzker, Reinhard / Kurzei, Oliver
2018-01-01
Theses
Electronic Resource
English
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