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1.
Proc Natl Acad Sci U S A ; 116(8): 3161-3170, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718392

RESUMO

Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1-3 (HNP1-3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information.


Assuntos
Predisposição Genética para Doença , Sepse/genética , alfa-Defensinas/genética , Alelos , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Variações do Número de Cópias de DNA/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Camundongos , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piroptose/genética , Piroptose/imunologia , Receptores Purinérgicos P2X7/genética , Fatores de Risco , Sepse/sangue , Sepse/patologia , alfa-Defensinas/antagonistas & inibidores , alfa-Defensinas/imunologia
2.
ACS Nano ; 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29856606

RESUMO

The increasing prevalence of antibacterial resistance globally underscores the urgent need to the update of antibiotics. Here, we describe a strategy for inducing the self-assembly of a host-defense antimicrobial peptide (AMP) into nanoparticle antibiotics (termed nanobiotics) with significantly improved pharmacological properties. Our strategy involves the myristoylation of human alpha-defensin 5 (HD5) as a therapeutic target and subsequent self-assembly in aqueous media in the absence of exogenous excipients. Compared with its parent HD5, the C-terminally myristoylated HD5 (HD5-myr)-assembled nanobiotic exhibited significantly enhanced broad-spectrum bactericidal activity in vitro. Mechanistically, it selectively killed Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) through disruption of the cell wall and/or membrane structure. The in vivo results further demonstrated that the HD5-myr nanobiotic protected against skin infection by MRSA and rescued mice from E. coli-induced sepsis by lowering the systemic bacterial burden and alleviating organ damage. The self-assembled HD5-myr nanobiotic also showed negligible hemolytic activity and substantially low toxicity in animals. Our findings validate this design rationale as a simple yet versatile strategy for generating AMP-derived nanobiotics with excellent in vivo tolerability. This advancement will likely have a broad impact on antibiotic discovery and development efforts aimed at combating antibacterial resistance.

3.
BMC Pulm Med ; 17(1): 218, 2017 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-29282039

RESUMO

BACKGROUND: Early onset of lung injury is considerable common after cardiac surgery and is associated with increasing in morbidity and mortality, but current clinical predictors for the occurrence of this complication always have limited positive warning value. This study aimed to evaluate whether elevated plasma levels of human neutrophil peptides (HNPs) 1-3 herald impaired lung function in infants and young children after cardiac surgery necessitating cardiopulmonary bypass (CPB). METHODS: Consecutive children younger than 3 years old who underwent cardiac surgery were prospectively enrolled. Plasma concentrations of HNPs 1-3 and inflammatory cytokines were measured before, and immediately after CPB, as well as at 1 h, 12 h, and 24 h after CPB. RESULTS: Thirty patients were enrolled, 18 (60%) of whom were infants. Plasma levels of HNPs 1-3 and the pro-inflammatory cytokine interleukin-6 (IL-6) significantly increased immediately after CPB (P < 0.001), while IL-8 increased 1 h after the CPB operation (P = 0.002). The anti-inflammatory cytokine IL-10 levels were also significantly elevated immediately after CPB compared with the baseline (P < 0.001). The stepwise multiple linear regression analysis showed that the plasma HNPs 1-3 levels immediately after CPB was independent correlated with the declined lung function, as reflected by the PaO2/FiO2 ratio on the first 2 days after operation (for the first day: OR, -1.067, 95% CI, -0.548 to -1.574; P < 0.001; for the second day: OR, -0.667, 95% CI, -0.183 to -1.148; P = 0.009) and prolonged mechanical ventilation time (OR, 0.039, 95% CI, 0.005 to 0.056; P = 0.011). Plasma levels of HNPs 1-3 and IL-10 returned to the baseline values, while IL-6 and IL-8 levels remained significantly higher than baseline 24 h after CPB (P ≤ 0.01). CONCLUSIONS: Elevated HNPs 1-3 levels immediately after CPB correlate with impaired lung function, and HNPs 1-3 could serve as a quantifiable early alarmin biomarker for onset of lung injury in infants and young children undergoing cardiac surgery with CPB.

4.
Am J Respir Crit Care Med ; 196(12): 1559-1570, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-28850247

RESUMO

RATIONALE: Efficient elimination of pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine-1-phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. OBJECTIVES: To investigate the role of S1PR3 in antibacterial immunity during sepsis. METHODS: Loss- and gain-of-function experiments were performed using cell and murine models. S1PR3 levels were determined in patients with sepsis and healthy volunteers. MEASUREMENTS AND MAIN RESULTS: S1PR3 protein levels were up-regulated in macrophages upon bacterial stimulation. S1pr3-/- mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild-type bone marrow-derived macrophages rescued S1pr3-/- mice from lethal sepsis. S1PR3-overexpressing macrophages further ameliorated the mortality rate of sepsis. Loss of S1PR3 led to markedly decreased bacterial killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated the macrophage bactericidal function and improved survival rates in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3-/- macrophages due to impaired recruitment of vacuolar protein-sorting 34 to the phagosomes. In addition, S1RP3 expression levels were elevated in monocytes from patients with sepsis. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status, and preferable outcomes. CONCLUSIONS: S1PR3 signaling drives bacterial killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens.


Assuntos
Morte Celular/imunologia , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/imunologia , Sepse/imunologia , Transdução de Sinais/imunologia , Animais , Morte Celular/genética , Modelos Animais de Doenças , Intervalo Livre de Doença , Humanos , Camundongos , Transdução de Sinais/genética , Regulação para Cima/genética , Regulação para Cima/imunologia
5.
Sci Rep ; 7: 39961, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-28079123

RESUMO

Monocyte apoptosis is a key mechanism that orchestrates host immune responses during sepsis. TRIM22 is constitutively expressed at high levels in monocytes and plays important roles in the antiviral response and inflammation. Overexpression of TRIM22 interferes with the clonogenic growth of monocytic cells, suggesting that TRIM22 may regulate monocyte survival. However, the effect of TRIM22 on monocyte apoptosis remains unknown. In the present report, lipopolysaccharides (LPS)-primed human peripheral blood monocytes expressing higher levels of TRIM22 were more sensitive to apoptosis. This phenomenon was also observed in TRIM22-overexpressing THP-1 monocytes and was associated with the activation of caspase-9 and caspase-3, as well as the increased expression and oligomerization of the pro-apoptotic protein Bak. Similar expression patterns of TRIM22 and Bak were also observed in LPS-primed, apoptotic human peripheral blood monocytes. In addition, the deletion of either the RING domain or the SPRY domain of TRIM22 significantly attenuated TRIM22-mediated monocyte apoptosis and decreased Bak expression and oligomerization. Furthermore, in monocytes from septic patients, TRIM22 levels were down-regulated and positively correlated with Bak levels. Taken together, these results indicate that TRIM22 plays a critical role in monocyte apoptosis by regulating Bak oligomerization and may have a potential function in the pathogenesis of sepsis.


Assuntos
Apoptose , Antígenos de Histocompatibilidade Menor/metabolismo , Proteínas Repressoras/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Adulto , Idoso , Apoptose/efeitos dos fármacos , Domínio B30.2-SPRY/genética , Caspase 3/metabolismo , Caspase 9/metabolismo , Células Cultivadas , Regulação para Baixo , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Multimerização Proteica , Proteínas Repressoras/genética , Sepse/metabolismo , Sepse/patologia , Proteínas com Motivo Tripartido/genética
6.
Anesthesiology ; 126(1): 128-139, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27792045

RESUMO

BACKGROUND: Transient receptor potential melastatin 2 is a Ca-permeable cation channel abundantly expressed in macrophages. Trpm2 mice showed exacerbated infection and mortality during polymicrobial sepsis, which is associated with inefficient bacterial killing in macrophages. However, the mechanism of transient receptor potential melastatin 2 regulating bacterial killing remains unknown. METHODS: Trpm2 mice were intraperitoneally injected with Escherichia coli. The survival rate (n = 21) and bacterial burden (n = 5) were assessed. The processes of phagosome maturation and phagosome-lysosome fusion in peritoneal macrophages were extensively studied. The impact of increasing intracellular Ca concentration on bacterial clearance in macrophages (n = 3) and on survival rate of Trpm2 mice infected with E. coli (n = 21) was investigated. RESULTS: Trpm2 mice exhibited increased mortality (85% vs. 54%; P < 0.01) and aggravated bacterial burden during E. coli sepsis. Trpm2 peritoneal macrophages infected with E. coli showed dampened recruitment of lysosomal-associated membrane protein 1 and impaired phagosome maturation evidenced by a decrease in the accumulation of early endosome antigen 1, whereas a normal acquisition of Ras-related protein in brain 5. Increasing the cytosolic Ca concentration in Trpm2 peritoneal macrophages via ionomycin treatment facilitated early endosome antigen 1 recruitment to Ras-related protein in brain 5 and phagosomal localization of lysosomal-associated membrane protein 1 and consequently enhanced bactericidal activity. Adoptive transfer of ionomycin-treated Trpm2 peritoneal macrophages improved bacterial clearance and survival (67% vs. 29%; P < 0.01) in Trpm2 mice challenged with E. coli. CONCLUSIONS: Transient receptor potential melastatin 2 plays a critical role in host defense against invading bacteria via promoting phagosome maturation through facilitation of early endosome antigen 1 recruitment.


Assuntos
Infecções por Escherichia coli/metabolismo , Fagossomos/metabolismo , Sepse/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Técnicas de Cultura de Células , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sobrevida
7.
Anesthesiology ; 123(2): 409-22, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26200183

RESUMO

BACKGROUND: Sepsis is characterized by an inappropriate systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Sphingosine 1-phosphate receptor 2 (S1PR2) modulates endotoxin-induced inflammation in endothelium. However, as a highly expressed S1P receptor in macrophages, its role in regulating macrophage response to bacterial infection remains unclear. METHODS: Cecal ligation and puncture or intratracheal instillation of Escherichia coli was induced in wild-type or S1pr2-deficient mice. The antibacterial ability of cell-specific S1PR2 was tested in bone marrow reconstitution mice or mice with macrophage-specific deletion. Signaling molecules responsible for S1PR2-mediated phagocytosis were also measured in the bone marrow-derived macrophages. In addition, S1PR2 expression levels and its correlation with severity of sepsis were determined in critically ill patients (n = 25). RESULTS: Both genetic deletion and pharmaceutical inhibition of S1PR2 significantly limited bacterial burden, reduced lung damage, and improved survival (genetic deletion, 0% in S1pr2 vs. 78.6% in S1pr2, P < 0.001; pharmaceutical inhibition, 9.1% in vehicle vs. 22.2% in S1PR2 antagonist, P < 0.05). This protection was attributed to the enhanced phagocytic function of S1PR2-deficient macrophages (mean fluorescent intensity, 2035.2 ± 202.1 vs. 407.8 ± 71.6, P < 0.001). Absence of S1PR2 in macrophage inhibits RhoA-dependent cell contraction and promotes IQGAP1-Rac1-dependent lamellipodial protrusion, whose signaling pathways depend on extracellular stimulators. In septic patients, increased S1PR2 levels in peripheral blood mononuclear cells were positively correlated with the severity of sepsis (r = 0.845, P < 0.001). CONCLUSIONS: This study implies that S1PR2, as a critical receptor in macrophage, impairs phagocytosis and antimicrobial defense in the pathogenesis of sepsis. Interventions targeting S1PR2 signaling may serve as promising therapeutic approaches for sepsis.


Assuntos
Especificidade de Hospedeiro/fisiologia , Macrófagos/metabolismo , Fagocitose/fisiologia , Receptores de Lisoesfingolipídeo/deficiência , Sepse/metabolismo , Transdução de Sinais/fisiologia , Animais , Células Cultivadas , Feminino , Macrófagos/imunologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sepse/imunologia
8.
Anesthesiology ; 122(2): 374-86, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25264597

RESUMO

BACKGROUND: Hepcidin is a master regulator of iron metabolism primarily produced by the liver. Markedly increased hepcidin levels have been observed in septic individuals, while decreased hepatic hepcidin expression has been demonstrated in liver diseases that tend to develop into sepsis. However, the role of liver hepcidin in sepsis remains unknown. METHODS: Mouse hepatic hepcidin expression was silenced using adenovirus-mediated hepcidin-specific short hairpin RNA injected via the tail vein. Sepsis was induced by cecal ligation and puncture, and the outcome (n = 23 for hepcidin knockdown mice, n = 15 for controls) and pathogenic changes (n = 5) related to sepsis were evaluated. The impact of alteration of iron status on the survival rate of hepatic hepcidin knockdown mice (n = 18 to 19) was also investigated. RESULTS: Disruption of liver hepcidin expression increased serum iron level (537.8 ± 28.1 µg/dl [mean ± SD] vs. 235.9 ± 62.2 µg/dl; P < 0.05) and reduced iron content in the spleen macrophages at the steady state. Hepatic hepcidin knockdown mice not only showed increased 7-day mortality (73.9% vs. 46.7%; P < 0.05), but also had exacerbated organ damage and oxidative stress, as well as compromised host inflammatory responses and bacterial clearance at 24 h after polymicrobial sepsis. Treating the hepatic hepcidin knockdown mice with low-iron diet plus iron chelation decreased systemic iron content (serum level: 324.0 ± 67.4 µg/dl vs. 517.4 ± 13.4 µg/dl; P < 0.05) and rescued the mice from lethal sepsis (7-day survival: 36.8% vs. 83.3%; P < 0.01). CONCLUSIONS: Hepatic hepcidin plays an important role in sepsis through regulation of iron metabolism. The findings may have potential therapeutic implications for liver diseases in which hepcidin expression is decreased.


Assuntos
Hepcidinas/genética , Hepcidinas/fisiologia , Ferro/metabolismo , Sepse/prevenção & controle , Animais , Contagem de Colônia Microbiana , Ferro/sangue , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , NADPH Oxidases/metabolismo , Estado Nutricional/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Sepse/metabolismo , Sepse/microbiologia , Baço/efeitos dos fármacos , Baço/metabolismo
9.
Biomed Res Int ; 2014: 180109, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25210703

RESUMO

Sepsis is a leading cause of mortality and morbidity in the critical illness. Multiple immune inflammatory processes take part in the pathogenesis of sepsis. Defensins are endogenous antimicrobial peptides with three disulphide bonds created by six cysteine residues. Besides the intrinsic microbicidal properties, defensins are active players which modulate both innate and adaptive immunity against various infections. Defensins can recruit neutrophils, enhance phagocytosis, chemoattract T cells and dendritic cells, promote complement activation, and induce IL-1ß production and pyrotosis. Previous publications have documented that defensins play important roles in a series of immune inflammatory diseases including sepsis. This review aims to briefly summarize in vitro, in vivo, and genetic studies on defensins' effects as well as corresponding mechanisms within sepsis and highlights their promising findings which may be potential targets in future therapies of sepsis.


Assuntos
Defensinas/metabolismo , Interleucina-1beta/metabolismo , Fagocitose/imunologia , Sepse/imunologia , Imunidade Adaptativa , Defensinas/genética , Defensinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Humanos , Imunidade Inata , Interleucina-1beta/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Sepse/tratamento farmacológico , Sepse/patologia , Linfócitos T/imunologia
10.
Crit Care ; 18(4): 470, 2014 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-25096529

RESUMO

INTRODUCTION: The production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. Hepcidin is a ß-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infectious and inflammatory diseases. We therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury. METHODS: Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (CLP) surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the 7-day survival rate were assessed. The levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated. RESULTS: The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased the mortality (53.33% in Ad-shHepc1 treated mice versus 12.5% in Ad-shNeg treated mice, P <0.05). The knockdown of hepcidin in airway epithelial cells also led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages. Moreover, alveolar macrophages form the airway epithelial cell-derived hepcidin knockdown mice showed impaired phagocytic ability than those from the control mice. CONCLUSIONS: Airway epithelial cell-derived hepcidin plays an important role in CLP induced acute lung injury. The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages.


Assuntos
Lesão Pulmonar Aguda/microbiologia , Líquido da Lavagem Broncoalveolar/microbiologia , Hepcidinas/fisiologia , Ferro/metabolismo , Sepse/microbiologia , Lesão Pulmonar Aguda/etiologia , Animais , Coinfecção , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Progressão da Doença , Células Epiteliais/imunologia , Células Epiteliais/fisiologia , Hepcidinas/imunologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Respiratório , Sepse/complicações , Taxa de Sobrevida
11.
Am J Respir Crit Care Med ; 188(2): 201-12, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23721075

RESUMO

RATIONALE: Triggering receptor expressed on myeloid cells-2 (TREM-2) is a cell surface receptor primarily expressed on macrophages and monocyte-derived cells. TREM-2 not only functions as a regulator of inflammatory response, but also serves as a phagocytic receptor for bacteria. However, the role of TREM-2 in sepsis remains unknown. OBJECTIVES: To investigate whether TREM-2 plays a role in sepsis. METHODS: The manner of expression of TREM-2 was evaluated in patients with sepsis and in polymicrobial septic mouse model induced by the cecum ligation and puncture approach. Recombinant mouse TREM-2 was used to block the effect of TREM-2. Bone marrow-derived myeloid cells (BMMCs) that overexpress TREM-2 were administrated into septic mice at various times after cecum ligation and puncture. MEASUREMENTS AND MAIN RESULTS: The expression levels of TREM-2 were up-regulated in patients with sepsis and septic mice. The kinetics of TREM-2 expression in polymicrobial sepsis was comparable with that of bacteria burden in peritoneal lavage fluid. Blocking the effect of TREM-2 resulted in markedly increased mortality and bacterial burden in polymicrobial sepsis. Administration of TREM-2-overexpressing BMMCs significantly reduced the mortality, even when it was administered 4 hours after the initiation of sepsis. However, injection of TREM-2-overexpressing BMMCs into LPS-challenged endotoxemia mice did not improve the survival rate. The protective effect of TREM-2 in polymicrobial sepsis was not associated with its antiinflammatory properties, but it enhanced bacterial clearance in vivo. Furthermore, administration of TREM-2-overexpressing BMMCs improved the organ injury. CONCLUSIONS: TREM-2 plays an important role in the host defense response to sepsis by enhancing bacterial clearance.


Assuntos
Carga Bacteriana/imunologia , Glicoproteínas de Membrana/biossíntese , Células Mieloides/imunologia , Receptores Imunológicos/biossíntese , Sepse/imunologia , Adenoviridae/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ascite/metabolismo , Coinfecção/imunologia , Feminino , Humanos , Interleucina-13/imunologia , Interleucina-4/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Fagocitose/imunologia , Proteínas Recombinantes , Sepse/microbiologia , Regulação para Cima
12.
J Clin Pharm Ther ; 38(2): 150-5, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23464988

RESUMO

WHAT IS KNOWN AND OBJECTIVES: The serotoninergic receptor 5-hydroxytryptamine (serotonin) receptor 3 (HTR3) is instrumental in the regulation of nausea and emesis (vomiting).This study investigated whether common genomic variations of the A and B subunits of HTR3 (HTR3A, HTR3B) are associated with the incidence of post-operative vomiting in a Chinese Han population. METHODS: Two hundred and thirty-one female Chinese Han patients undergoing gynaecological surgery with standardized general anaesthesia were recruited for the study. Clinical symptoms after surgery were recorded and direct DNA sequencing was performed to detect polymorphisms of HTR3A and HTR3B. RESULTS: Five single nucleotide polymorphisms (SNPs) in HTR3A and HTR3B were found, with R(2)  > 0·8 and minor allele frequency > 10%. One of these (rs3758987 in HTR3B) was statistically associated with vomiting, after adjusting for body weight, body mass index and duration of general anaesthesia in dominant and additive models (P = 0·047 and P = 0·034). WHAT IS NEW AND CONCLUSION: The HTR3B rs3758987 SNP might serve as a predictor of post-operative vomiting in Chinese Han patients undergoing gynaecological laparoscopic surgery.


Assuntos
Náusea e Vômito Pós-Operatórios/genética , Receptores 5-HT3 de Serotonina/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Frequência do Gene , Genótipo , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
13.
Mol Med Rep ; 7(4): 1117-22, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23426900

RESUMO

Inflammatory and immune responses, as well as melatonin secretion, are affected by circadian regulation. Abnormal circadian rhythm of melatonin release has been reported to be associated with the later stages of sepsis; however, its role in the early stages of sepsis is unclear. We studied 11 septic and 11 non-septic patients in our intensive care unit (ICU). Peripheral blood was drawn at 4-h intervals on the first day, beginning at 2:00 p.m., over a total period of 24 h. Plasma levels of melatonin, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured by radioimmunoassay or enzyme-linked immunosorbent assay (ELISA). Messenger RNA levels of circadian genes Cry-1 and Per-2 were analyzed using quantitative real-time PCR. Results show the circadian rhythm of melatonin secretion was altered in the early stages of sepsis. The melatonin secretion acrophase occurred earlier in septic patients at 6:00 p.m., compared with at 2:00 a.m. in non-septic ICU patients. Compared with the non-septic group, both Cry-1 and Per-2 expression were significantly decreased while TNF-α and IL-6 expression were significantly increased in septic patients [TNF-α, 64.1 (43.6-89.1) vs. 11.4 (10.4-12.5) ng/ml; IL-6, 41.2 (35.7-50.8) vs. 19.1 (16-136.7) ng/ml; median (range), both P=0.04]. The peak concentrations of TNF-α and IL-6 were shown to be in concordance with the rhythm of melatonin secretion. The circadian rhythm of melatonin secretion and circadian gene expression were altered in the early stages of sepsis, which likely led to the changes in pro-inflammatory cytokine release. These findings shed light on the potential link between circadian rhythm and the progression of early-stage sepsis.


Assuntos
Ritmo Circadiano/genética , Interleucina-6/biossíntese , Melatonina/genética , Sepse/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Idoso , Criptocromos/biossíntese , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Melatonina/metabolismo , Pessoa de Meia-Idade , Proteínas Circadianas Period/biossíntese , Sepse/genética , Sepse/patologia
14.
Crit Care ; 16(3): R91, 2012 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-22616947

RESUMO

INTRODUCTION: Acute lung injury (ALI) after cardiac surgery is associated with a high postoperative morbidity and mortality, but few predictors are known for the occurrence of the complication. This study evaluated whether elevated plasma levels of soluble receptor for advanced glycation end products (sRAGE) and S100A12 reflected impaired lung function in infants and young children after cardiac surgery necessitating cardiopulmonary bypass (CPB). METHODS: Consecutive children younger than 3 years after cardiac surgery were prospectively enrolled and assigned to ALI and non-ALI groups, according to the American-European Consensus Criteria. Plasma concentrations of sRAGE and S100A12 were measured at baseline, before, and immediately after CPB, as well as 1 hour, 12 hours, and 24 hours after operation. RESULTS: Fifty-eight patients were enrolled and 16 (27.6%) developed postoperative ALI. Plasma sRAGE and S100A12 levels increased immediately after CPB and remained significantly higher in the ALI group even 24 hour after operation (P < 0.01). In addition, a one-way MANOVA revealed that the overall sRAGE and S100A12 levels were higher in the ALI group than in the non-ALI group immediately after CPB (P < 0.001). The multivariate logistic regression analysis showed that the plasma sRAGE level immediately after CPB was an independent predictor for postoperative ALI (OR, 1.088; 95% CI, 1.011 to 1.171; P = 0.025). Increased sRAGE and S100A12 levels immediately after CPB were significantly correlated with a lower PaO2/FiO2 ratio (P < 0.01) and higher radiographic lung-injury score (P < 0.01), as well as longer mechanical ventilation time (sRAGEN: r = 0.405; P = 0.002; S100A12N: r = 0.322; P = 0.014), longer surgical intensive care unit stay (sRAGEN: r = 0.421; P = 0.001; S100A12N: r = 0.365; P = 0.005) and hospital stay (sRAGEN: r = 0.329; P = 0.012; S100A12N: r = 0.471; P = 0.001). CONCLUSIONS: Elevated sRAGE and S100A12 levels correlate with impaired lung function, and sRAGE is a useful early biomarker of ALI in infants and young children undergoing cardiac surgery.


Assuntos
Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/diagnóstico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Receptores Imunológicos/sangue , Lesão Pulmonar Aguda/etiologia , Biomarcadores/sangue , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Projetos Piloto , Valor Preditivo dos Testes , Estudos Prospectivos , Receptor para Produtos Finais de Glicação Avançada
15.
Int J Infect Dis ; 16(7): e558-64, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22609014

RESUMO

OBJECTIVES: Sepsis is a leading cause of death in critically ill patients, and apoptosis plays a major role in the pathophysiology of sepsis. Elevated levels of circulating nucleosomes released by apoptotic cells have been detected in patients with severe sepsis and septic shock. The aim of this study was to evaluate the diagnostic/prognostic value of circulating nucleosomes in sepsis. METHODS: Seventy-four newly admitted patients with an estimated length of stay in the intensive care unit of more than 48 h, were prospectively enrolled as cohort 1. The second independent cohort (cohort 2) consisted of 91 post-surgery patients. Patients receiving chemotherapy, those with AIDS, those on steroid treatment, and those undergoing transplants were excluded. Levels of circulating nucleosomes within 24h of admission in both cohorts, and for cohort 1 also on days 3, 5, and 7 and a last time-point of ICU discharge or at imminent death, were measured and analyzed for their capacity to predict sepsis. The severity of the inflammatory response and organ dysfunction were assessed by cytokine levels and sepsis scores. RESULTS: Nucleosome levels on admission in septic patients were significantly higher than those in non-septic controls in both of the cohorts. The area under the receiver operating characteristic curve for admission nucleosome levels to differentiate septic patients from non-septic patients was 0.70 (95% confidence interval (CI) 0.51-0.88) in cohort 1, 0.66 (95% CI 0.55-0.79) in cohort 2, and 0.67 (95% CI 0.55-0.79) in all of the subjects. After multiple logistic regression analysis, circulating nucleosomes remained as an independent predictor of sepsis. Furthermore, the levels of circulating nucleosomes on admission were significantly correlated with the inflammatory response and organ dysfunction in sepsis. Meanwhile, a trend was observed for admission levels of circulating nucleosomes in non-survivors to be higher than those in survivors. CONCLUSIONS: The level of circulating nucleosomes in the serum has a predictive value for sepsis and organ dysfunction and may serve as a candidate biomarker for the diagnosis/prognosis of sepsis. Further studies are warranted to confirm the present findings.


Assuntos
Biomarcadores/sangue , Estado Terminal , Insuficiência de Múltiplos Órgãos/diagnóstico , Nucleossomos/metabolismo , Sepse/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/sangue , Valor Preditivo dos Testes , Prognóstico , Sepse/sangue , Síndrome de Resposta Inflamatória Sistêmica , Adulto Jovem
16.
Curr Drug Targets ; 12(2): 256-62, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21126227

RESUMO

Sepsis is a common and frequently a fatal syndrome. Though, there is steady progress in the management of sepsis, further reduction of its mortality is still hampered by the lack of specific remedies. Recent advances in the understanding of the pathophysiology of sepsis and innovations in drug design have enabled researchers to develop new strategies for the treatment of this complicated condition in a more efficient way. Among these, a variety of small synthetic compounds with the molecular weight lower than 1000Da are emerging rapidly. This review highlights the advances of these small molecules in the treatment of sepsis, which are categorized into the following seven groups according to their pharmaceutical targets: LPS sequestrants and TLR4 antagonists, C5a receptor antagonists, inhibitors of macrophage migration inhibitory factor, inhibitors of QseC signaling, A3 adenosine receptor agonists and A2A adenosine receptor antagonists, estrogen receptor ß agonists and caspase inhibitors. Most of the compounds have shown effectiveness in preclinical studies and displayed little or no toxicity. These small molecular compounds are potential candidates for further therapeutic development of sepsis.


Assuntos
Sepse/tratamento farmacológico , Animais , Humanos , Terapia de Alvo Molecular , Sepse/metabolismo , Sepse/fisiopatologia
17.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 39(5): 477-82, 2010 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-20936721

RESUMO

OBJECTIVE: To construct a eukaryotic expression plasmid containing human triggering receptor expressed on myeloid cells-1(TREM-1) gene. METHODS: The entire gene coding region of human TREM-1 was amplified from total RNA of human peripheral blood by means of RT-PCR. The fragment of TREM-1 was cloned to vector pUCm-T. After digestion by restriction endonuclease BamH I and Pst I, the fragment was subcloned into the eukaryotic expressing vector pEGFP-C3. This recombinant vector was transfected into 293 cells using liposome. The expression level of TREM-1 was determined by fluorescence microscope and Western blot assay. The recombinant TREM-1 vector was transfected into THP-1 cells. After stimulation with 100 ng/ml LPS for 24 h, the mRNA levels of TNF-α and IL-1ß were measured using RT-PCR. RESULT: The expression vector was constructed, and the result of the DNA sequencing showed that the constructed plasmid containing the TREM-1 gene. Fluorescence microscope and Western blot analysis showed that TREM-1 protein was expressed in 293 cells successfully. After transfection into THP-1 cells, recombinant TREM-1 could upregulate the mRNA levels of TNF-α and IL-1ß. CONCLUSION: Eukaryotic expression plasmid pEGFP-TREM-1 is successfully constructed and showed biological activity.


Assuntos
Vetores Genéticos , Glicoproteínas de Membrana/genética , Plasmídeos/genética , Receptores Imunológicos/genética , Células Cultivadas , Humanos , Transfecção , Receptor Gatilho 1 Expresso em Células Mieloides
18.
Anesthesiology ; 112(6): 1428-34, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20502117

RESUMO

BACKGROUND: Human neutrophil peptides 1-3 are endogenous cationic antimicrobial peptides implicated in host defense against microbes. The genes encoding human neutrophil peptides 1-3 (DEFA1/DEFA3) exhibit copy number variations. This study was designed to determine whether DEFA1/DEFA3 copy number variations conferred susceptibility to infection-induced complications such as severe sepsis. METHODS: This case-control study was performed in 179 patients with severe sepsis and 233 healthy blood donors and was replicated in an independent cohort of 112 cases and 118 controls. Plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 were detected. RESULTS: The genotype of DEFA1/DEFA3 with more than eight copies was more frequent in patients with severe sepsis than in controls (55.9% vs. 31.3%; P = 1.13 x 10, odds ratio 2.77, 95% confidence interval 1.85-4.16). After adjustment for age and gender, logistic regression analysis confirmed the association of the genotype of more than eight copies with an increased risk of severe sepsis (P = 2.25 x 10, odds ratio 2.66, 95% confidence interval 1.69-4.19). This established association was replicated in a second age- and gender-matched case-control cohort (P = 0.02, odds ratio 1.90, 95% confidence interval 1.11-3.27). Furthermore, compared with those with fewer copies, the patients carrying more than eight copies of DEFA1/DEFA3 presented significantly lower plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 (P = 0.039, 0.017, 0.030, and 0.029, respectively). CONCLUSIONS: DEFA1/DEFA3 is an important genetic component participating in host immune response to severe sepsis. A higher copy number of DEFA1/DEFA3 (>8 copies) is significantly associated with the risk of severe sepsis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Dosagem de Genes/genética , Predisposição Genética para Doença/genética , Sepse/genética , alfa-Defensinas/genética , Idoso , Grupo com Ancestrais do Continente Asiático/etnologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Sepse/etnologia
19.
Ann Surg Oncol ; 15(12): 3494-502, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18830757

RESUMO

BACKGROUND: Transcriptional regulation of the putative tumor suppressor gene X-linked inhibitor of apoptosis protein-associated factor 1 (XAF1) by promoter methylation has been related to tumor progression in gastric and bladder cancer. The aim of this study was to investigate the methylation status and expression level of XAF1 in human hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) treated with liver transplantation (LT), and to evaluate potential predictive value for tumor recurrence. METHODS: The expression level and methylation status of XAF1 in three liver cancer cell lines (SMMC-7721, HepG2, and Hep3B) and 65 cases of HBV-associated HCC following LT were analyzed by RT-PCR (RT, reverse-transcriptase), immunohistochemistry, and methylation-specific polymerase chain reaction (PCR). RESULTS: XAF1 transcripts were not observed or present at low levels in liver cancer cell lines and were restored by treatment with demethylating agent 5-aza-2'-deoxycytidine (5-Aza-dC). In vivo, methylation status was associated with protein level of XAF1 (P < 0.001) and serum level of alpha-fetoprotein (AFP) (P = 0.009). The expression pattern of XAF1 was associated with portal vein tumor thrombi (PVTT), preoperative AFP level, tumor size, and recurrence. Multivariate analysis revealed that expression level of XAF1 was an independent factor for predicting recurrence-free survival [hazard ratio 0.237, 95% confidence interval (CI) 0.095-0.592, P = 0.002]. However, no significant association was found between methylation status and the risk of tumor recurrence. CONCLUSION: Promoter hypermethylation is a critical, but not the sole, mechanism for gene silencing of XAF1 in HCC. Protein level of XAF1 may serve as a potential biomarker for tumor recurrence after LT.


Assuntos
Carcinoma Hepatocelular/genética , Metilação de DNA , Hepatite B/genética , Neoplasias Hepáticas/genética , Transplante de Fígado , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Azacitidina/farmacologia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/cirurgia , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatite B/complicações , Hepatite B/virologia , Vírus da Hepatite B/genética , Humanos , Técnicas Imunoenzimáticas , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Células Tumorais Cultivadas , Dedos de Zinco
20.
Crit Care ; 12(4): R106, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18706105

RESUMO

INTRODUCTION: Gelsolin is an actin-binding plasma protein that is part of an 'actin-scavenging' system. Studies suggest that plasma gelsolin may play a crucial role in the pathophysiology of sepsis. Little is known about the course of plasma gelsolin levels over time in patients with severe sepsis. The aim of the study was to investigate plasma gelsolin levels in severe septic patients and to determine whether these levels predict the severity or clinical outcome of severe sepsis. METHODS: Ninety-one patients who were diagnosed with severe sepsis at admission to a surgical intensive care unit were enrolled, and admission plasma gelsolin levels were recorded. Plasma gelsolin levels were recorded daily in 23 of these patients. Daily plasma gelsolin levels were recorded in an additional 15 nonseptic critically ill patients. Fifteen volunteers served as healthy control individuals. Plasma gelsolin levels were measured using an enzyme-linked immunosorbent assay. Concentrations of IL-6, IL-10 and tumour necrosis factor (TNF)-alpha were also measured on intensive care unit admission. RESULTS: The admission gelsolin levels were significantly decreased in severe sepsis (20.6 +/- 11.7 mg/l) compared with nonseptic critically ill patients (52.3 +/- 20.3 mg/l; P < 0.001) and healthy control individuals (126.8 +/- 32.0 mg/l; P < 0.001). Severe septic patients had increased IL-6 levels compared with nonseptic critically ill patients (20.0 +/- 10.7 pg/ml versus 11.4 +/- 13.9 pg/ml; P = 0.048), whereas no significant difference in IL-10 or TNF-alpha levels was observed (IL-10: 97.9 +/- 181.5 pg/ml versus 47.4 +/- 91.5 pg/ml, respectively [P = 0.425]; TNF-alpha: 14.2 +/- 13.9 pg/ml versus 6.9 +/- 5.3 pg/ml, respectively; P = 0.132). Survivors of severe sepsis exhibited substantial recovery of their depressed plasma gelsolin levels, whereas gelsolin levels in nonsurvivors remained at or below their depleted admission levels. CONCLUSION: Plasma gelsolin may be a valuable marker for severe sepsis. Recovery of depleted plasma gelsolin levels correlated with clinical improvement. The prognostic role of plasma gelsolin in critical illness requires further investigation in a large cohort.


Assuntos
Cuidados Críticos/tendências , Estado Terminal , Gelsolina/sangue , Sepse/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/diagnóstico , Sepse/etiologia , Fatores de Tempo
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