ABSTRACT
Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.
Subject(s)
Apoptosis/genetics , GTPase-Activating Proteins/antagonists & inhibitors , Hepatitis, Autoimmune/genetics , Liver/injuries , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Acetaminophen , Animals , Apoptosis/drug effects , Apoptosis/immunology , Carrier Proteins/genetics , Carrier Proteins/metabolism , Caspase 8/metabolism , Chemokine CCL2/blood , Concanavalin A , Disease Models, Animal , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/metabolism , Hepatocytes/pathology , Interleukin-6/blood , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein , Necrosis/genetics , Reactive Oxygen Species/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Tumor Necrosis Factor-alpha/bloodABSTRACT
The role of multidrug resistant Acinetobacter baumanii and its clinical relevance have been recently appreciated as a ubiquitous opportunistic nosocomial pathogen. Risk factors associated with A. baumanii infection include severe underlying diseases, previous surgery, invasive procedures, treatment with broad-spectrum antibiotics, length of hospital stay, admission to intensive care units (ICU). Carbapenem-multidrug resistant A. baumanii infections are probably associated to greater severity and more complications; in our cohort mortality was 49.3% and related mortality (within 72 hours) was 10.39%. However, severe underlying diseases probably play an important role in the clinical outcome of patients with MDR-C A. baumanii infection and controversy exists regarding the real mortality attributable to antimicrobial resistance because a high proportion of deaths took place > 7 days after diagnosis. Nevertheless, in our experience, carbapenem resistance, inappropriate therapy and monotherapy are associated to a higher mortality. Special attention should be paid to design well-controlled prospective clinical trials to determine the optimal antimicrobial therapy in critically ill patients suspected of having MDR Acinetobacter infection.
