Abstract
BackgroundNecroptosis is a newly recognized form of programmed cell death with characteristics of both necrosis and apoptosis. The role of necroptosis in hepatic damage during sepsis is poorly understood. In this study, we investigated the occurrence of necroptosis in hepatic damage, and its contribution to hepatic damage in a piglet model of lipopolysaccharide (LPS)-induced sepsis.MethodsTwo animal experiments were conducted. In trial 1, piglets were challenged with LPS and sacrificed at different time points after LPS challenge. In trial 2, piglets were pretreated with necrostatin-1, a specific inhibitor of necroptosis, prior to LPS challenge. Alterations in the hepatic structure and function, pro-inflammatory cytokine expression, and the necroptosis signaling pathway were investigated. Typical ultrastructural characteristics of cell necrosis was observed in the liver of LPS-challenged piglets.ResultsExpressions of critical components of necroptosis including kinases (RIP1, RIP3, and MLKL), mitochondrial proteins (PGAM5 and DRP1), and an intracellular damage-associated molecular pattern (HMGB1) were increased in the liver in a time-dependent manner, followed by hepatic inflammation, morphological damage, and dysfunction as manifested by elevated hepatic expression of IL-1β, IL-6 and TNF-α as well as increased serum AST and AKP activities and the AST/ALT ratio. Pretreatment with necrostatin-1 significantly reduced the expression of RIP1, RIP3 and MLKL as well as PGAM5, DRP1 and HMGB1, which subsequently led to obvious attenuation of hepatic inflammation and damage.ConclusionsOur study demonstrates that necroptosis occurs in the liver during sepsis and contributes to septic hepatic injury.
Highlights
Sepsis is a common and life-threatening illness that could lead to multiple organ failure, shock, and death as a result of an exaggerated inflammatory response to infection [1, 2]
We investigated the occurrence of necroptosis in hepatic damage, and its contribution to hepatic damage in a piglet model of lipopolysaccharide (LPS)-induced sepsis
Pretreatment with necrostatin-1 significantly reduced the expression of RIP1, RIP3 and mixed lineage kinase domain-like protein (MLKL) as well as phosphoglycerate mutase family member 5 (PGAM5), dynamin-related protein 1 (DRP1) and high-mobility group box 1 (HMGB1), which subsequently led to obvious attenuation of hepatic inflammation and damage
Summary
Sepsis is a common and life-threatening illness that could lead to multiple organ failure, shock, and death as a result of an exaggerated inflammatory response to infection [1, 2]. Severe septic liver damage may further cause multiple organ dysfunction syndrome [5]. Apoptosis and necrosis are recognized as two main modes of cell death contributing to the pathogenesis of liver diseases [7]. Necroptosis incorporates features of both necrosis and apoptosis, and is strictly regulated by receptor interacting protein kinase (RIP) 1 and 3 [9, 10]. RIP3 subsequently recruits and phosphorylates mixed lineage kinase domain-like protein (MLKL) to promote its oligomerization and translocation to plasma membrane, resulting in membrane rupture and necrotic cell death [9]. Necroptosis is a newly recognized form of programmed cell death with characteristics of both necrosis and apoptosis. The role of necroptosis in hepatic damage during sepsis is poorly understood. We investigated the occurrence of necroptosis in hepatic damage, and its contribution to hepatic damage in a piglet model of lipopolysaccharide (LPS)-induced sepsis
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