The role of the liver in the response to LPS: experimental and clinical findings

Jirillo, Emilio; Caccavo, Domenico; Magrone, Thea; Piccigallo, Ernesto; Amati, L.; Lembo, Annalisa; Kalis, Christoph; Gumenscheimer, Marina

doi:10.1179/096805102125000641

Cited by 115 publications

(95 citation statements)

References 82 publications

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“…28,29 Most of the LPS will be quickly inactivated and cleared by monocytes in blood, macrophages in tissue, and Kupffer cells in liver. [30][31][32] In our study, each dose of LPS injection was very low (0.0078 mg/rat), and the interval between injections was 2 days. This protocol is unlikely to lead to a continuous endotoxemia.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of LPS by polyethylene particles decreases bone attachment to implants

Xing

Pabst

Hasty

et al. 2006

Journal Orthopaedic Research

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Molecules absorbed on the surface of particulate wear debris may contribute to inflammatory reactions that lead to aseptic loosening of implants. Lipopolysaccharide (LPS), a bacterial endotoxin, can attach to many biomaterials and stimulate macrophages to secrete osteoclast-activating cytokines. We tested the adsorption of LPS by polyethylene particles in vitro and examined the biological effects of LPS absorption on bone remodeling around implants in vivo. Polyethylene particles were incubated in radiolabeled LPS solutions, and adsorption of LPS by the particles was quantified by radioassay. Because polyethylene particles are hydrophobic and less dense than water, they floated and clumped when incubated in a water solution of LPS, resulting in low adsorption of LPS. However, when particles were incubated in an ethanol solution of LPS, most of the LPS was adsorbed by the particles, and was resistant to washing with water. Triton X-100 (10%), however, effectively washed the LPS off the particles. In a rat model, the presence of polyethylene particles around the implant in the femoral canal decreased bone attachment to the implant at 6 weeks. Incubating the particles with LPS before implantation, or intermittent administration of LPS systemically, further decreased bone-implant attachment to similar extents, but had no effect on the bone density of the control side femurs. Our data indicate that polyethylene particles have high affinity for LPS, depending on many factors, especially the solvents of the LPS. Intermittent systemic administration of LPS affects bone remodeling but only occurs in the area containing polyethylene particles and titanium implants, supporting the hypothesis that the presence of polyethylene particles around implants can result in accumulation of LPS from exogenous sources. This may cause local levels of LPS that are high enough to affect bone remodeling around implants. ß

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Section: Discussionmentioning

confidence: 99%

Accumulation of LPS by polyethylene particles decreases bone attachment to implants

Xing

Pabst

Hasty

et al. 2006

Journal Orthopaedic Research

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“…19,35 Increased expression of MD2 and CD14 may render hepatocytes more susceptible to LPS-induced apoptosis, cell activation, and, ultimately, liver damage. 36 Furthermore, STAT1, a key signaling molecule for IFN-␥ induced by the initial P. acnes priming, was recently shown to play a central role in LPS-induced hepatocyte damage. 37 Thus, increased levels of MD-2 and CD14 on hepatocytes may contribute to direct LPS sensitivity in addition to cytokine (TNF-␣)-mediated changes in hepatocyte function.…”

Section: Discussionmentioning

confidence: 99%

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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“…The liver has a crucial, physiological role in LPS detoxification from the circulation, as bacterially derived products from the intestine translocate into the portal system, where they are sensed and cleared by Kupffer cells through interactions with cell surface CD14 (120). However, in the setting of liver disease, bacterial overgrowth, intestinal edema, and altered hepatic architecture result in the increased entry of LPS into the peripheral circulation, in turn activating Kupffer cells.…”

Section: Microbial Translocation In Liver Diseasementioning

confidence: 99%

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

2013

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SUMMARYIn pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections, the translocation of microbial products from the gastrointestinal (GI) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. Consistently, microbial translocation is not present in nonpathogenic SIV infections of natural host species.In vivostudies demonstrated that HIV/SIV-associated microbial translocation results from a series of immunopathological events occurring at the GI mucosa: (i) early and severe mucosal CD4+depletion, (ii) mucosal immune hyperactivation/persistent inflammation; (iii) damage to the integrity of the intestinal epithelium with enterocyte apoptosis and tight junction disruption; and (iv) subverted the gut microbiome, with a predominance of opportunistic bacteria. Directin situevidence of microbial translocation has been provided for SIV-infected rhesus macaques showing translocated microbial products in the intestinal lamina propria and distant sites. While the mechanisms by which microbial translocation causes immune activation remain controversial, a key pathogenic event appears to be innate immunity activation via Toll-like receptors and other pathogen recognition receptors. Accumulating clinical observations suggest that microbial translocation might affect HIV disease progression, response to therapy, and non-AIDS comorbidities. Given its detrimental effect on overall immunity, several interventions to prevent/block microbial translocation are currently under investigation as novel therapeutic agents for HIV/AIDS.

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The role of the liver in the response to LPS: experimental and clinical findings

Cited by 115 publications

References 82 publications

Accumulation of LPS by polyethylene particles decreases bone attachment to implants

Accumulation of LPS by polyethylene particles decreases bone attachment to implants

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

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

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