In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats
ABSTRACT Endoplasmic reticulum (ER)-related unfolded protein response (UPR) is mediated by PKR-like ER kinase (PERK), ATF6 and IRE1. PERK phosphorylates eukaryotic translation initiation factor-2alpha (eIF2alpha) to attenuate protein synthesis, including in NF-kappaB-dependent antiapoptotic proteins. We hypothesized that an altered UPR in the liver may sensitize cirrhotic livers to LPS-induced, TNFalpha-mediated apoptosis. Thus, we examined in vivo UPR and NF-kappaB activity in livers from cirrhotic and normal LPS-challenged rats.
Livers were harvested in rats that did or did not receive LPS.
Under baseline conditions, no UPR was found in normal livers while PERK/eIF2alpha and ATF6 pathways were activated in cirrhotic livers. After LPS, in normal livers, the PERK/eIF2alpha pathway was transiently activated. ATF6 and IRE1 were activated. In cirrhotic livers, the PERK/eIF2alpha pathway remained elevated. ATF6 and IRE1 pathways were altered. LPS-induced, NF-kappaB-dependent antiapoptotic proteins increased in normal livers whereas their expression was blunted at the posttranscriptional level in cirrhotic livers.
Cirrhotic livers exhibit partial UPR activation in the basal state and full UPR, although altered, after LPS challenge. Sustained eIF2alpha phosphorylation, a hallmark of cirrhotic liver UPR, is associated with a lack of LPS-induced accumulation of NF-kappaB-dependent antiapoptotic proteins which may sensitize cirrhotic livers to LPS/TNFalpha-mediated apoptosis.
- SourceAvailable from: Vanessa Stadlbauer
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- "In the context of Gramnegative infections, normal livers are protected against LPS-induced, TNF-αmediated apoptosis because of simultaneous induction of nuclear factor-κB (NF-κB)-dependent anti-apoptotic molecules . In contrast, cirrhotic livers are abnormally susceptible to LPS-induced, TNF-α-mediated apoptosis because NF-κB-target anti-apoptotic molecules cannot be properly induced . Therefore, in cirrhosis, infection-induced liver failure may be related not only to an excessive pro-inflammatory response but also to a decrease in the hepatic capacity of tolerance. "
ABSTRACT: Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gramnegative bacteria from intestinal origin, yet grampositive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports and in-depth review and a position statement on bacterial infections in cirrhosis.Journal of Hepatology 02/2014; 60(6). DOI:10.1016/j.jhep.2014.01.024 · 10.40 Impact Factor
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- "TNF, the major pro-inflammatory factor, has been shown to induce ER stress via increased ROS levels    . Endotoxin (LPS) induces ER stress  by activating all three pathways specific for UPR via corresponding sensors, IRE1, PERK, and ATF6  . Since endotoxin evokes a systemic immune response, one can conclude that systemic immune response induces ER stress via pro-inflammatory factors in a reactive oxygen species ( "
ABSTRACT: Inflammatory response has recently been shown to induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which either recovers proper ER function or activates apoptosis. Here we show that endotoxin (lipopolysaccharide = LPS) can lead to functional ER failure tentatively via a mitochondrion-dependent pathway in livers of rats. Histological examination did not reveal significant damage to liver in form of necroses. Electron microscopy displayed transparent rings appearing around morphologically unchanged mitochondria, which were identified as dilated ER. The spliced mRNA variant of X-box protein-1 (XBP1) and also the mRNA of 78 kDa glucose-regulated protein (GRP78) were up-regulated, both typical markers of ER stress. However, GRP78 was down-regulated at the protein level. A pro-apoptotic shift in the bax/bcl-XL mRNA ratio was not accompanied by translocation of apoptosis inducing factor (AIF) to the nucleus, suggesting that the cells entered a pre-apoptotic state, but apoptosis was not executed. Monooxygenase activity of p450, representing the detoxification system in ER, was decreased after administration of endotoxin. Biochemical analysis of proteins important for ER function revealed the impairment of protein folding, transport, and detoxification suggesting functional ER failure. We suggest that functional ER failure may be a reason for organ dysfunction upon excessive inflammatory response mediated by endotoxin.Biochimica et Biophysica Acta 04/2009; 1792(6):521-30. DOI:10.1016/j.bbadis.2009.03.004 · 4.66 Impact Factor
Article: Le sepsis dans la cirrhose[Show abstract] [Hide abstract]
ABSTRACT: Les patients atteints de cirrhose avec une infection bactérienne ont un risque élevé de développer un sepsis et des défaillances d’organe, voire d’évoluer vers le décès. L’infection spontanée du liquide d’ascite est l’infection la plus fréquente. Les infections bactériennes se répartissent de façon égale entre trois catégories: communautaires, associées aux soins et nosocomiales. L’incidence du sepsis dû aux bactéries multirésistantes augmente. Dans la cirrhose, le sepsis est associé à une réponse pro-inflammatoire excessive, qui pourrait être à l’origine de la défaillance de plusieurs organes (foie compris). Les mécanismes moléculaires de cette réponse inflammatoire excessive ne sont pas totalement compris. Chez les cirrhotiques avec sepsis, les défaillances d’organe majeures sont identifiées en utilisant le score SOFA (Sequential Organ Failure Assessment). Une antibiothérapie empirique, probabiliste, à large spectre et non néphrotoxique doit être débutée en urgence. Le choix des antibiotiques dépend du fait que le malade est à risque ou non d’infection à Enterobacteriaceae productrice de β-lactamase à spectre étendu. Chez les malades avec une infection spontanée du liquide d’ascite sans choc, l’administration intraveineuse d’albumine diminue la survenue d’un syndrome hépatorénal et améliore la survie. Deux essais randomisés ont montré que les systèmes extracorporels de suppléance hépatique (MARS® et Promotheus®) amélioraient l’encéphalopathie hépatique mais pas la survie. Le sepsis bactérien peut être prévenu par l’administration de norfloxacine chez les malades avec une hémorragie digestive ou dans le cadre de la prévention primaire ou secondaire de l’infection spontanée du liquide d’ascite.Réanimation 01/2012; 22(2). DOI:10.1007/s13546-012-0536-z