Heme oxygenase-1–mediated autophagy protects against hepatocyte cell death and hepatic injury from infection/sepsis in mice

Abstract

Adaptive responses to sepsis are necessary to prevent organ failure and death. Cellular signaling responses that limit cell death and structural damage allow a cell to withstand insult from sepsis to prevent irreversible organ dysfunction. One such protective pathway to reduce hepatocellular injury is the up-regulation of heme oxygenase-1 (HO-1) signaling. HO-1 is up-regulated in the liver in response to multiple stressors, including sepsis and lipopolysaccharide (LPS), and has been shown to limit cell death. Another recently recognized rudimentary cellular response to injury is autophagy. The aim of these investigations was to test the hypothesis that HO-1 protects against hepatocyte cell death in experimental sepsis in vivo or LPS in vitro via induction of autophagy. These data demonstrate that both HO-1 and autophagy are up-regulated in the liver after cecal ligation and puncture (CLP) in C57BL/6 mice or in primary mouse hepatocytes after treatment with LPS (100 ng/mL). CLP or LPS results in minimal hepatocyte cell death. Pharmacological inhibition of HO-1 activity using tin protoporphyrin or knockdown of HO-1 prevents the induction of autophagic signaling in these models and results in increased hepatocellular injury, apoptosis, and death. Furthermore, inhibition of autophagy using 3-methyladenine or small interfering RNA specific to VPS34, a class III phosphoinositide 3-kinase that is an upstream regulator of autophagy, resulted in hepatocyte apoptosis in vivo or in vitro. LPS induced phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), in part, via HO-dependent signaling. Moreover, inhibition of p38 MAPK prevented CLP-or LPS-induced autophagy. Conclusion: Sepsis or LPS-induced autophagy protects against hepatocellular death, in part via an HO-1 p38 MAPK-dependent signaling. Further investigations are needed to elucidate how autophagic signaling prevents apoptosis and cell death. (HEPATOLOGY 2011;53:2053-2062 S epsis is a systemic inflammatory response that occurs as a consequence of an infectious insult. It is a significant health problem, with a mortality rate of 30%-60%. The predominant cause of morbidity and mortality is the development of multiple system organ dysfunction with subsequent organ failure. The cause of early organ dysfunction in the setting of sepsis is secondary both to cellular activation by bacterial products, including lipopolysaccharide (LPS), elaborated inflammatory cytokines, as well as hemodynamic abnormalities, leading to decreased oxygen delivery. Interestingly, early organ dysfunction from sepsis usually is not associated with cell death. Several studies have illustrated that in response to infection and sepsis, cells will undergo a metabolic shutdown as an adaptive response to protect against tissue injury and long-term structural damage. 1 Mitochondria are responsible for greater than 90% of the body's oxygen consumption through oxidative phosphorylation and adenosine triphosphate (ATP) production, with less than 2% of this consumption leading to the production ...

ZnPP reduces autophagy and induces apoptosis, thus aggravating liver ischemia/reperfusion injury in vitro

“…The expression of mitochondrial cytochrome c and Bcl-2 protein expression were decreased in the ZIR group. Based on these findings (11), as well as those of previous studies, we hypothesized that the decrease in HO-1 expression induced by ZnPP may reduce autophagy, thus increasing liver cell injury, and that this may partly occur through the activation of the mitochondrial apoptotic pathway.…”

“…It has been demonstrated that the induction of heme oxygenase-1 (HO-1) attenuates liver cell injury, and that preconditioning with protoporphyrin Ⅸ zinc accentuates liver damage (10). A previous study reported that HO-1 attenuates liver injury by inducing autophagy and inhibiting cell apoptosis, and that a decrease in HO-1 activity increases cell apoptosis and thus accentuates liver injury (11). Therefore, it may be of interest to investigate the role of ZnPP in liver ischemia/reperfusion (IR) injury.…”

Autophagy in sepsis: Degradation into exhaustion?

“…51 Conversely, administration of chloroquine abolishes autophagic flux, which results in the elevation of serum transaminase levels. 14 Compelling evidence confirms that autophagy in the liver is induced during the initial 4 h after CLP but declines after this point until 24 h. 11,14,19,36,51 The blockade of autophagic flux is demonstrated by reduced LAMP1 expression, accumulation of SQSTM1 and lack of colocalization of autophagosomes with lysosomes.…”

“…16,17 In support of this notion, newly tested therapeutic agents in animal models have targeted modulation of the same molecular pathway-autophagy. 10,[18][19][20][21][22] In this review, we discuss the role of autophagy in sepsis.…”

Autophagy Protects from Ventilator-induced Lung Injury Partly through Activation of Haem Oxygenase-1 Pathway

“…In fact, many reports have suggested that HO-1 signalling pathways have an important role in the regulation of autophagy (10) hepatocyte cell death and hepatic injury from infection/sepsis in mice (12). Moreover, in myocardial dysfunction, HO-1 can prevent cardiac dysfunction in streptozotocin-diabetic mice by reducing inflammation, oxidative stress, apoptosis and enhancing autophagy (13).…”