Liver in sepsis and systemic inflammatory response syndrome

Szabó, Gyöngyi; Romics, L; Frendl, György

doi:10.1016/s1089-3261(02)00058-2

Cited by 154 publications

(97 citation statements)

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“…[2][3][4] Signals mediated via the pattern recognition receptors TLR2 and TLR4 are pivotal in recognition of gram-negative and gram-positive pathogens. [12][13][14] Here we report that priming of mice with the gram-positive bacterium P. acnes leads to selective sensitization to TLR4-but not TLR2-mediated inflammatory cytokine activation and liver injury.…”

Section: Discussionmentioning

confidence: 99%

“…1 Activation of the proinflammatory cytokine cascade, including tumor necrosis factor ␣ (TNF-␣), interleukin (IL)-1, IL-6, IL-12, IL-18, and interferon␥ (IFN-␥), plays an important role in the pathophysiology and clinical outcome of liver failure. [1][2][3][4] Many features of liver failure resemble abnormalities associated with severe endotoxin shock, including hepatocyte damage, hemodynamic compromise, and coma. 2,5 In animals, sensitization with heat-killed Propionibacterium acnes (P. acnes), a weak gram-positive bacteria, results in enhanced lipopolysaccharide (LPS) sensitivity leading to overactivation of the proinflammatory cytokine cascade and liver failure.…”

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confidence: 99%

“…[1][2][3][4] Many features of liver failure resemble abnormalities associated with severe endotoxin shock, including hepatocyte damage, hemodynamic compromise, and coma. 2,5 In animals, sensitization with heat-killed Propionibacterium acnes (P. acnes), a weak gram-positive bacteria, results in enhanced lipopolysaccharide (LPS) sensitivity leading to overactivation of the proinflammatory cytokine cascade and liver failure. 6 -8 P. acnes-induced sensitization is thought to be mediated by IFN-␥ and requires IL-12 and IL-18 activation.…”

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Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands byP. acnes involves up-regulation of MD-2 in mice

et al. 2004

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Lipopolysaccharide (LPS) triggers cytokine production through Toll-like receptor 4 (TLR4), which shares downstream signaling pathways with TLR2. We investigated the roles of TLR2 and TLR4 in Propionibacterium acnes (P. acnes)-primed, LPS-induced liver damage using selective TLR ligands. Stock LPS induced interleukin 8 in both TLR4-and TLR2-expressing human embryonic kidney (HEK) 293 cells. Purified LPS (TLR4 ligand) activated HEK/TLR4 cells, while peptidoglycan and lipoteichoic acid (TLR2 ligands) activated HEK/TLR2 cells, respectively. In mice, P. acnes priming resulted in increased liver messenger RNA (mRNA) and serum levels of tumor necrosis factor ␣, interleukin 12, and interferon ␥ (IFN-␥) by both stock LPS and purified LPS challenges compared with nonprimed controls. In contrast, P. acnes failed to sensitize to TLR2 ligands (peptidoglycan ؉ lipoteichoic acid). In the liver, P. acnes-priming was associated with up-regulation of TLR4 and MD-2 proteins, and subsequent LPS challenge further increased MD-2 and CD14 mRNA levels. The lack of sensitization to TLR2 ligands by P. acnes correlated with no increase in hepatic TLR1 or TLR6 mRNA. In vitro, P. acnes pretreatment desensitized RAW macrophages to a secondary stimulation via both TLR2 and TLR4. However, IFN-␥ could selectively prevent desensitization to TLR4 but not to TLR2 ligands. Furthermore, P. acnes induced production of IFN-␥ in vivo as well as in isolated splenocytes. In vitro, P. acnes-primed Hepa 1-6 hepatocytes but not RAW macrophages produced increased MD-2 and CD14 mRNA levels after an LPS challenge. In conclusion, P. acnes priming to selective TLR4-mediated liver injury is associated with up-regulation of TLR4 and MD-2 and is likely to involve IFN-␥ and prevent TLR4 desensitization by P. acnes. (HEPATOLOGY 2004;40:555-564.)

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Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands byP. acnes involves up-regulation of MD-2 in mice

et al. 2004

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“…Another remarkable finding was the localization of lysozyme immunoreactivity. Since lysozyme is an enzyme responsible for bacteriolysis, (16) its immunoreactivity is localized to cells performing phagocytosis, such as Kupffer cells. However, in the present patient, CD68 þ cells and some hepatocytes showed immunoreactivity for lysozyme.…”

Section: Discussionmentioning

confidence: 99%

A patient with severe hypercalcemia in multiple organ dysfunction syndrome: Role of elevated circulating 1α,25(OH)2vitamin D levels

Kazama

Yamamoto

Oya

et al. 2010

Journal of Bone and Mineral Research

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A 54-year-old man was transferred to our ICU because of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). He died after 38 days of intensive care. During treatment, his serum calcium (Ca) levels continued to increase and reached 3.95 mmol/L, while the ionized Ca levels reached 2.30 mmol/L before his death. He presented with severe kidney injury, pancreatitis, and hemorrhagic gastric erosion that worsened his prognosis; these were possibly associated with the hypercalcemia. His circulating 1a,25-dihydroxyvitamin D [1,25(OH) 2 D] level was elevated (75.7 to 204 pg/mL), whereas the levels of 25-hydroxyvitamin D, parathyroid hormone, and parathyroid hormone-related peptide were not. Liver histology revealed immunoreactivity for 25-hydroxyvitamin D 1a-hydroxylase (CYP27B1) in some of the hepatocytes, in which the localization pattern was similar to that of lysozyme-positive hepatocytes. Our ICU has previously encountered 22 similar MODS patients who presented with hypercalcemia over the last 8 years. SIRS with severe kidney and liver injuries are common clinical findings in hypercalcemic patients with MODS. Of the 23 hypercalcemic MODS patients, including the present patient, 17 had circulating 1,25(OH) 2 D levels exceeding 70 pg/mL despite severe kidney injury. Extrarenal activation of CYP27B1 seems to play a role in the development of hypercalcemia in this disease condition. Clinicians need to be aware that severe hypercalcemia may occur in MODS patients. ß

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“…Sepsis-induced multiple organ dysfunction has a high mortality and the liver plays a central pathophysiological role (1). The liver produces pro-coagulant factors, complement and acute phase proteins.…”

Section: Introductionmentioning

confidence: 99%

Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

Dear

Leelahavanichkul

Aponte

et al. 2007

Critical Care Medicine

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Objective-Sepsis-induced multi-organ failure continues to have a high mortality. The liver is an organ central to the disease pathogenesis. The objective of this study was to identify the liver proteins that change in abundance with sepsis and, therefore, identify new drug targets. Design-Proteomic discovery study and drug target validation Setting-Research institute laboratorySubjects-Three month old C57BL/6 mice Interventions-We used a mouse model of sepsis based on cecal ligation and puncture (CLP) but with fluid and antibiotic resuscitation. Liver proteins that changed in abundance were identified by difference in-gel electrophoresis (DIGE). We compared liver proteins from 6 hr post-CLP to shamoperated mice ('early proteins') and 24 hr post-CLP with 6 hr post-CLP ('late proteins'). Proteins that changed in abundance were identified by tandem mass spectrometry. We then inhibited the receptor for one protein and determined the effect on sepsis-induced organ dysfunction.Results-The liver proteins that changed in abundance after sepsis had a range of functions such as acute phase proteins, coagulation, ER stress, oxidative stress, apoptosis, mitochondrial proteins and nitric oxide metabolism. We found that cyclophilin increased in abundance after CLP. When the receptor for this protein, CD147, was inhibited sepsis-induced renal dysfunction was reduced. There was also a significant reduction in serum cytokine production when CD147 was inhibited.Conclusion-By applying proteomics to a clinically relevant mouse model of sepsis we identified a number of novel proteins that changed in abundance. The inhibition of the receptor for one of these proteins, cyclophilin, attenuated sepsis-induced acute renal failure. The application of proteomics to sepsis research can facilitate the discovery of new therapeutic targets.

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Liver in sepsis and systemic inflammatory response syndrome

Cited by 154 publications

References 86 publications

Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands byP. acnes involves up-regulation of MD-2 in mice

Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands byP. acnes involves up-regulation of MD-2 in mice

A patient with severe hypercalcemia in multiple organ dysfunction syndrome: Role of elevated circulating 1α,25(OH)2vitamin D levels

Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

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