The acute phase response is an orchestrated response to tissue injury, infection or inflammation. A prominent feature of this response is the induction of acute phase proteins, which are involved in the restoration of homeostasis. Cytokines are important mediators of the acute phase response. Uncontrolled and prolonged action of cytokines is potentially harmful, therefore mechanisms exist which limit the activity of cytokines; these include soluble cytokine receptors and receptor antagonists. The cytokine signal is transmitted into the cell via membrane‐bound receptors. Different intracellular signalling pathways are activated by different cytokine‐receptor interactions. Eventually, cytokine‐inducible transcription factors interact with their response elements in the promotor region of acute phase genes and transcription is induced. Systemic inflammation results in a systemic acute phase response. However, local inflammatory or injurious processes in the liver may also induce an acute phase response, for example after partial hepatectomy and during hepatic fibrosis. The acute phase proteins induced in these conditions probably act to limit proteolytic and/or fibrogenic activity and tissue damage. The possible function of the acute phase protein α2‐macroglobulin in hepatic fibrosis is discussed in some detail. © 1997 John Wiley & Sons, Ltd.

Plasma nitrite and nitrate determinations are increasingly being used in clinical chemistry as markers for the activity of nitric oxide synthase and the production of nitric oxide radicals. However, a systematic evaluation of the determination of nitrite and nitrate in plasma has not been performed. In this study the recovery and stability of nitrite and nitrate in whole blood and in plasma, the relation between nitrite and nitrate concentrations in plasma, and possible sources of artifacts were investigated. The main conclusions are: (a) Recovery of nitrite and nitrate from plasma is near-quantitative (87%) and reproducible; (b) nitrite and nitrate are stable in (frozen) plasma for at least 1 year; (c) nitrite in whole blood is very rapidly (> 95% in 1 h) oxidized to nitrate, and therefore plasma nitrite determination alone is meaningless; (d) the ranges of nitrite and nitrate concentrations in plasma samples of 26 healthy persons are 1.3-13 mumol/L (mean 4.2 mumol/L) and 4.0-45.3 mumol/L (mean 19.7 mumol/L), respectively; (e) plasma nitrite and nitrate concentrations were not correlated (nitrite as % of total nitrite + nitrate varied from 3.9% to 88% in plasma samples); and (f) plasma samples should be deproteinized, and background controls for each sample should be included in the assay, to avoid measuring artifactually high nitrite and nitrate concentrations in plasma.

AST and ALT elevations had also been reported in patients with SARS caused by SARS-CoV. (37) Several case reports have described severe LFT abnormalities (18,38,39) or acute-on-chronic (40,41) liver failure in patients with COVID-19. Zhang et al. (33) reported that 1 of 82 deceased patients with COVID-19 had a hepatic cause of death, although it was not clear whether this patient had pre-existing liver disease.Elevated ALP was reported in 2%-5% of patients, (5,11,25,42) and elevated GGT was reported in 13%-54% of patients (weighted average: 23%). (5,11,19,42) The prevalence of total bilirubin elevations ranged between 1% and 18% of patients with COVID-19 on admission. (4,5,15,16,18,25,35,43) It should be realized, aRtICle INFoRMatIoN:

Endotoxin-induced cholestasis is mainly caused by an impaired canalicular secretion. Mrp2, the canalicular multispecific organic anion transporter, is strongly downregulated in this situation, and canalicular bile salt secretion is also reduced. We hypothesized that other adenosine triphosphate-binding cassette (ABC) transporters may compensate for the decreased transport activity to protect the cell from cytokine-induced oxidative damage. Therefore, we examined the expression of ABC-transport proteins in membrane fractions of whole liver and of isolated hepatocytes of endotoxin-treated rats and performed reversetranscriptase polymerase chain reaction (RT-PCR) on mRNA isolated from these livers. In addition, the localization of these transporters was examined using confocal scanning laser microscopy. By 6 hours after endotoxin administration, we found a clear increase of mrp1 mRNA and protein, whereas mrp2 mRNA and protein were decreased. This was confirmed in isolated hepatocytes. In addition, mdr1b mRNA was strongly increased, whereas mdr1a and mdr2 mRNA did not change significantly. Both the mRNA and protein levels of the sister of P-glycoprotein (spgp), the recently cloned bile salt transporter, decreased. After endotoxin treatment, the normally sharply delineated canalicular staining of mrp2 and spgp had changed to a fuzzy pattern, suggesting localization in a subapical compartment. We conclude that endotoxin-induced cholestasis is caused by decreased mrp2 and spgp levels, as well as an abnormal localization of these proteins. The simultaneous up-regulation of mrp1 and mdr1b may confer resistance to hepatocytes against cytokine-induced metabolic stress. (HEPATOLOGY 1998;28:1637-1644.)Excretion of a large variety of endogenous and exogenous compounds from hepatocytes into bile is an adenosine triphosphate (ATP)-dependent process, predominantly performed by members of the P-glycoprotein (Pgp) subfamily and the multidrug-resistance protein (MRP) subfamily of the ATP-binding cassette (ABC) protein superfamily. 1,2 At least four members of the Pgp subfamily are located at the canalicular membrane of rodent liver: mdr1a, mdr1b, mdr2, and spgp. In normal rodent liver, mdr1a and mdr1b are present at low levels. Overexpression of mouse mdr1a/mdr1b confers multidrug resistance against a broad variety of natural product drugs. 3,4 The main physiological function of these multidrug-resistance proteins is presumably the transport of bulky amphiphilic compounds, such as cationic drugs, hydrophobic peptides, steroids, and atypical glycolipids, across the canalicular membrane. 1,4,5 The expression of mdr2 in normal rodent liver is high. This transporter functions as a flippase that translocates phosphatidylcholine across the membrane. 6 From pig liver, Childs et al. cloned part of another member of the Pgp subfamily: the sister gene of Pgp (spgp). 7 Most recently, Gerloff et al. cloned the full-length cDNA of spgp from rat liver. 8 They provided evidence that spgp, which is exclusively present in the liver, most likely is t...

Oxidative stress (OxS) is considered a major factor in the pathophysiology of inflammatory chronic liver diseases, including non-alcoholic liver disease (NAFLD). Chronic impairment of lipid metabolism is closely related to alterations of the oxidant/antioxidant balance, which affect metabolism-related organelles, leading to cellular lipotoxicity, lipid peroxidation, chronic endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Increased OxS also triggers hepatocytes stress pathways, leading to inflammation and fibrogenesis, contributing to the progression of non-alcoholic steatohepatitis (NASH). The antioxidant response, regulated by the Nrf2/ARE pathway, is a key component in this process and counteracts oxidative stress-induced damage, contributing to the restoration of normal lipid metabolism. Therefore, modulation of the antioxidant response emerges as an interesting target to prevent NAFLD development and progression. This review highlights the link between disturbed lipid metabolism and oxidative stress in the context of NAFLD. In addition, emerging potential therapies based on antioxidant effects and their likely molecular targets are discussed.

Ursodeoxycholic acid (UDCA) is used in the treatment of cholestatic liver diseases, but its mechanism of action is not yet well defined. The aim of this study was to explore the protective mechanisms of the taurine-conjugate of UDCA (tauroursodeoxycholic acid [TUDCA]) against glycochenodeoxycholic acid (GCDCA)-induced apoptosis in primary cultures of rat hepatocytes. Hepatocytes were exposed to GCDCA, TUDCA, the glyco-conjugate of UDCA (GUDCA), and TCDCA. The phosphatidylinositol-3 kinase pathway (PI3K) and nuclear factor-B were inhibited using LY 294002 and adenoviral overexpression of dominant-negative I B, respectively. The role of p38 and extracellular signalregulated protein kinase mitogen-activated protein kinase (MAPK) pathways were investigated using the inhibitors SB 203580 and U0 126 and Western blot analysis. Transcription was blocked by actinomycin-D. Apoptosis was determined by measuring caspase-3, -9, and -8 activity using fluorimetric enzyme detection, Western blot analysis, immunocytochemistry, and nuclear morphological analysis. Our results demonstrated that uptake of GCDCA is needed for apoptosis induction. TUDCA, but not TCDCA and GUDCA, rapidly inhibited, but did not delay, apoptosis at all time points tested. However, the protective effect of TUDCA was independent of its inhibition of caspase-8. Up to 6 hours of preincubation with TUDCA before addition of GCDCA clearly decreased GCDCAinduced apoptosis. At up to 1.5 hours after exposure with GCDCA, the addition of TUDCA was still protective. This protection was dependent on activation of p38, ERK MAPK, and PI3K pathways, but independent of competition on the cell membrane, NF-B activation, and transcription. In conclusion, TUDCA contributes to the protection against GCDCA-induced mitochondria-controlled apoptosis by activating survival pathways. Supplemental material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/supplmat/index.html). (HEPATOLOGY 2004;39:1563-1573

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We found that PCT and acute phase proteins such as CRP are induced by similar pathways. The liver appears to be a major source of PCT production. Thus, PCT may be considered an acute phase protein. The different kinetics of PCT, rather than a fundamentally different afferent pathway, may explain its putative diagnostic potential to discriminate bacterial infection from other causes of inflammation.