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1.
J Lipid Res ; 62: 100011, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500240

RESUMO

Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and detoxification. Cholesteryl ester transfer protein (CETP) is an LT/LBP member, but its impact on LPS metabolism and sepsis outcome is unclear. Here, we performed fluorescent LPS transfer assays to assess the ability of CETP to bind and transfer LPS. The effects of intravenous (iv) infusion of purified LPS or polymicrobial infection (cecal ligation and puncture [CLP]) were compared in transgenic mice expressing human CETP and wild-type mice naturally having no CETP activity. CETP displayed no LPS transfer activity in vitro, but it tended to reduce biliary excretion of LPS in vivo. The CETP expression in mice was associated with significantly lower basal plasma lipid levels and with higher mortality rates in both models of endotoxemia and sepsis. Furthermore, CETPTg plasma modified cytokine production of macrophages in vitro. In conclusion, despite having no direct LPS binding and transfer property, human CETP worsens sepsis outcomes in mice by altering the protective effects of plasma lipoproteins against endotoxemia, inflammation, and infection.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol
2.
J Lipid Res ; 56(7): 1363-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26023073

RESUMO

Quantitation of plasma lipopolysaccharides (LPSs) might be used to document Gram-negative bacterial infection. In the present work, LPS-derived 3-hydroxymyristate was extracted from plasma samples with an organic solvent, separated by reversed phase HPLC, and quantitated by MS/MS. This mass assay was combined with the limulus amebocyte lysate (LAL) bioassay to monitor neutralization of LPS activity in biological samples. The described HPLC/MS/MS method is a reliable, practical, accurate, and sensitive tool to quantitate LPS. The combination of the LAL and HPLC/MS/MS analyses provided new evidence for the intrinsic capacity of plasma lipoproteins and phospholipid transfer protein to neutralize the activity of LPS. In a subset of patients with systemic inflammatory response syndrome, with documented infection but with a negative plasma LAL test, significant amounts of LPS were measured by the HPLC/MS/MS method. Patients with the highest plasma LPS concentration were more severely ill. HPLC/MS/MS is a relevant method to quantitate endotoxin in a sample, to assess the efficacy of LPS neutralization, and to evaluate the proinflammatory potential of LPS in vivo.


Assuntos
Análise Química do Sangue/métodos , Caranguejos Ferradura , Lipopolissacarídeos/sangue , Proteínas de Membrana/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lipopolissacarídeos/química , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem
3.
Front Immunol ; 12: 658404, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163471

RESUMO

Chronic kidney disease induces disruption of the intestinal epithelial barrier, leading to gut bacterial translocation. Here, we appreciated bacterial translocation by analyzing circulating lipopolysaccharides (LPS) using two methods, one measuring only active free LPS, and the other quantifying total LPS as well as LPS lipid A carbon chain length. This was done in end-stage renal disease (ESRD) patients and healthy volunteers (HV). We observed both higher LPS concentration in healthy volunteers and significant differences in composition of translocated LPS based on lipid A carbon chain length. Lower LPS activity to mass ratio and higher concentration of high-density lipoproteins were found in HV, suggesting a better plasma capacity to neutralize LPS activity. Higher serum concentrations of soluble CD14 and pro-inflammatory cytokines in ESRD patients confirmed this hypothesis. To further explore whether chronic inflammation in ESRD patients could be more related to LPS composition rather than its quantity, we tested the effect of HV and patient sera on cytokine secretion in monocyte cultures. Sera with predominance of 14-carbon chain lipid A-LPS induced higher secretion of pro-inflammatory cytokines than those with predominance of 18-carbon chain lipid A-LPS. TLR4 or LPS antagonists decreased LPS-induced cytokine production by monocytes, demonstrating an LPS-specific effect. Thereby, septic inflammation observed in ESRD patients may be not related to higher bacterial translocation, but to reduced LPS neutralization capacity and differences in translocated LPS subtypes.


Assuntos
Translocação Bacteriana , Suscetibilidade a Doenças , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Adulto , Idoso , Biomarcadores , Estudos de Casos e Controles , Comorbidade , Citocinas/sangue , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Endotoxemia/diagnóstico , Endotoxemia/etiologia , Feminino , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Transplante de Rim , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo
4.
J Leukoc Biol ; 81(2): 567-77, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17062602

RESUMO

The ability of human neutrophils to express a variety of genes encoding inflammatory mediators is well documented, and mounting evidence suggests that neutrophil-derived cytokines and chemokines contribute to the recruitment of discrete leukocyte populations at inflammatory sites. Despite this, our understanding of the signaling intermediates governing the generation of inflammatory cytokines by neutrophils remains fragmentary. Here, we report that inhibitors of the p38 MAPK and MEK pathways substantially diminish the release of (and in the case of p38 inhibitors, the gene expression of) several inflammatory cytokines in neutrophils stimulated with LPS or TNF. In addition, various NF-kappaB inhibitors were found to profoundly impede the inducible gene expression and release of inflammatory cytokines in these cells. The MAPK inhibitors did not affect NF-kappaB activation; instead, the transcriptional effects of the p38 MAPK inhibitor appear to involve transcriptional factor IID. Conversely, the NF-kappaB inhibitors failed to affect the activation of MAPKs. Finally, the MAPK inhibitors were found to prevent the activation a key component of the translational machinery, S6 ribosomal protein, in keeping with their post-transcriptional impact on cytokine generation. To our knowledge, this constitutes the first demonstration that in neutrophils, the inducible expression of proinflammatory cytokines by physiological stimuli largely reflects the ability of the latter to activate NF-kappaB and selected MAPK pathways. Our data also raise the possibility that NF-kappaB or MAPK inhibitors could be useful in the treatment of inflammatory disorders in which neutrophils predominate.


Assuntos
Citocinas/biossíntese , Sistema de Sinalização das MAP Quinases/imunologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Neutrófilos/imunologia , Ácidos Borônicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Citocinas/imunologia , Humanos , Inflamação/metabolismo , Leupeptinas/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Neutrófilos/efeitos dos fármacos , Nitrilas/farmacologia , Prolina/análogos & derivados , Prolina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Sulfonas/farmacologia , Tiocarbamatos/farmacologia
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