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1.
Proc Natl Acad Sci U S A ; 111(8): 3068-73, 2014 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-24469805

RESUMEN

Extracellular high-mobility group box (HMGB)1 mediates inflammation during sterile and infectious injury and contributes importantly to disease pathogenesis. The first critical step in the release of HMGB1 from activated immune cells is mobilization from the nucleus to the cytoplasm, a process dependent upon hyperacetylation within two HMGB1 nuclear localization sequence (NLS) sites. The inflammasomes mediate the release of cytoplasmic HMGB1 in activated immune cells, but the mechanism of HMGB1 translocation from nucleus to cytoplasm was previously unknown. Here, we show that pharmacological inhibition of JAK/STAT1 inhibits LPS-induced HMGB1 nuclear translocation. Conversely, activation of JAK/STAT1 by type 1 interferon (IFN) stimulation induces HMGB1 translocation from nucleus to cytoplasm. Mass spectrometric analysis unequivocally revealed that pharmacological inhibition of the JAK/STAT1 pathway or genetic deletion of STAT1 abrogated LPS- or type 1 IFN-induced HMGB1 acetylation within the NLS sites. Together, these results identify a critical role of the JAK/STAT1 pathway in mediating HMGB1 cytoplasmic accumulation for subsequent release, suggesting that the JAK/STAT1 pathway is a potential drug target for inhibiting HMGB1 release.


Asunto(s)
Núcleo Celular/metabolismo , Proteína HMGB1/metabolismo , Janus Quinasa 1/metabolismo , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/fisiología , Acetilación , Transporte Activo de Núcleo Celular/efectos de los fármacos , Transporte Activo de Núcleo Celular/fisiología , Análisis de Varianza , Animales , Bencimidazoles/farmacología , Western Blotting , Cromatografía Liquida , Ensayo de Inmunoadsorción Enzimática , Escherichia coli , Inmunohistoquímica , Interferón Tipo I/farmacología , Lipopolisacáridos , Ratones , Piridonas/farmacología , Transducción de Señal/efectos de los fármacos , Espectrometría de Masas en Tándem
2.
Am J Physiol Lung Cell Mol Physiol ; 311(2): L507-16, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27343190

RESUMEN

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia (CAP). Granzyme A (GzmA) is a serine protease produced by a variety of cell types involved in the immune response. We sought to determine the role of GzmA on the host response during pneumococcal pneumonia. GzmA was measured in bronchoalveolar lavage fluid (BALF) harvested from CAP patients from the infected and contralateral uninfected side and in lung tissue slides from CAP patients and controls. In CAP patients, GzmA levels were increased in BALF obtained from the infected lung. Human lungs showed constitutive GzmA expression by both parenchymal and nonparenchymal cells. In an experimental setting, pneumonia was induced in wild-type (WT) and GzmA-deficient (GzmA(-/-)) mice by intranasal inoculation of S. pneumoniae In separate experiments, WT and GzmA(-/-) mice were treated with natural killer (NK) cell depleting antibodies. Upon infection with S. pneumoniae, GzmA(-/-) mice showed a better survival and lower bacterial counts in BALF and distant body sites compared with WT mice. Although NK cells showed strong GzmA expression, NK cell depletion did not influence bacterial loads in either WT or GzmA(-/-) mice. These results implicate that GzmA plays an unfavorable role in host defense during pneumococcal pneumonia by a mechanism that does not depend on NK cells.


Asunto(s)
Granzimas/fisiología , Neumonía Neumocócica/enzimología , Streptococcus pneumoniae/inmunología , Animales , Líquido del Lavado Bronquioalveolar , Estudios de Casos y Controles , Femenino , Humanos , Inmunidad Celular , Células Asesinas Naturales/fisiología , Pulmón/enzimología , Pulmón/inmunología , Pulmón/microbiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Infiltración Neutrófila , Neumonía Neumocócica/inmunología , Neumonía Neumocócica/microbiología
3.
Thorax ; 69(11): 1034-42, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25179663

RESUMEN

BACKGROUND: Streptococcus pneumoniae is the most commonly identified pathogen in community-acquired pneumonia (CAP). Myeloid-related protein (MRP) 8/14 is a major component of neutrophils that is released upon infection or injury. MRP8/14 is essential for protective immunity during infection by a variety of micro-organisms through its capacity to chelate manganese and zinc. Here, we aimed to determine the role of MRP8/14 in pneumococcal pneumonia. METHODS: MRP8/14 was determined in bronchoalveolar lavage fluid (BALF) and serum of CAP patients, in lung tissue of patients who had succumbed to pneumococcal pneumonia, and in BALF of healthy subjects challenged with lipoteichoic acid (a component of the gram-positive bacterial cell wall) via the airways. Pneumonia was induced in MRP14 deficient and normal wildtype mice. The effect of MRP8/14 on S. pneumoniae growth was studied in vitro. RESULTS: CAP patients displayed high MRP8/14 levels in BALF, lung tissue and serum. Healthy subjects challenged with lipoteichoic acid demonstrated elevated MRP8/14 in BALF. Likewise, mice with pneumococcal pneumonia had high MRP8/14 levels in lungs and the circulation. MRP14 deficiency, however, was associated with reduced bacterial growth and lethality, in the absence of notable effects on the inflammatory response. High zinc levels strongly inhibited growth of S. pneumoniae in vitro, which was partially reversed by MRP8/14. CONCLUSIONS: In sharp contrast to its previously reported host-protective role in several infections, the present results reveal that in a model of CAP, MRP8/14 is misused by S. pneumoniae, facilitating bacterial growth by attenuating zinc toxicity toward the pathogen.


Asunto(s)
Calgranulina B/metabolismo , Pulmón/metabolismo , Neumonía Neumocócica/metabolismo , Streptococcus pneumoniae/patogenicidad , Animales , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Femenino , Humanos , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neumonía Neumocócica/microbiología , Neumonía Neumocócica/patología
4.
PLoS Pathog ; 8(10): e1002987, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23133376

RESUMEN

Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis. Myeloid related protein 8 (MRP8, S100A8) and MRP14 (S100A9) are the most abundant cytoplasmic proteins in neutrophils. They can form MRP8/14 heterodimers that are released upon cell stress stimuli. MRP8/14 reportedly exerts antimicrobial activity, but in acute fulminant sepsis models MRP8/14 has been found to contribute to organ damage and death. We here determined the role of MRP8/14 in K. pneumoniae sepsis originating from the lungs, using an established model characterized by gradual growth of bacteria with subsequent dissemination. Infection resulted in gradually increasing MRP8/14 levels in lungs and plasma. Mrp14 deficient (mrp14(-/-)) mice, unable to form MRP8/14 heterodimers, showed enhanced bacterial dissemination accompanied by increased organ damage and a reduced survival. Mrp14(-/-) macrophages were reduced in their capacity to phagocytose Klebsiella. In addition, recombinant MRP8/14 heterodimers, but not MRP8 or MRP14 alone, prevented growth of Klebsiella in vitro through chelation of divalent cations. Neutrophil extracellular traps (NETs) prepared from wildtype but not from mrp14(-/-) neutrophils inhibited Klebsiella growth; in accordance, the capacity of human NETs to kill Klebsiella was strongly impaired by an anti-MRP14 antibody or the addition of zinc. These results identify MRP8/14 as key player in protective innate immunity during Klebsiella pneumonia.


Asunto(s)
Calgranulina B/inmunología , Infecciones por Klebsiella/inmunología , Klebsiella pneumoniae/inmunología , Neutrófilos/inmunología , Neumonía Bacteriana/inmunología , Sepsis/inmunología , Transportadoras de Casetes de Unión a ATP/inmunología , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Calgranulina B/genética , Calgranulina B/metabolismo , Línea Celular , Humanos , Infecciones por Klebsiella/microbiología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/microbiología , Macrófagos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis , Neumonía Bacteriana/microbiología , Sepsis/microbiología
5.
Nat Med ; 13(9): 1042-9, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17767165

RESUMEN

To identify new components that regulate the inflammatory cascade during sepsis, we characterized the functions of myeloid-related protein-8 (Mrp8, S100A8) and myeloid-related protein-14 (Mrp14, S100A9), two abundant cytoplasmic proteins of phagocytes. We now demonstrate that mice lacking Mrp8-Mrp14 complexes are protected from endotoxin-induced lethal shock and Escherichia coli-induced abdominal sepsis. Both proteins are released during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the active component that induces intracellular translocation of myeloid differentiation primary response protein 88 and activation of interleukin-1 receptor-associated kinase-1 and nuclear factor-kappaB, resulting in elevated expression of tumor necrosis factor-alpha (TNF-alpha). Using phagocytes expressing a nonfunctional Toll-like receptor 4 (TLR4), HEK293 cells transfected with TLR4, CD14 and MD2, and by surface plasmon resonance studies in vitro, we demonstrate that Mrp8 specifically interacts with the TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. Therefore Mrp8-Mrp14 complexes are new inflammatory components that amplify phagocyte activation during sepsis upstream of TNFalpha-dependent effects.


Asunto(s)
Calgranulina A/fisiología , Calgranulina B/fisiología , Endotoxinas/toxicidad , Choque Séptico/fisiopatología , Receptor Toll-Like 4/fisiología , Animales , Calgranulina A/deficiencia , Calgranulina B/genética , Línea Celular Tumoral , Células Cultivadas , Citometría de Flujo , Humanos , Ligandos , Lipopolisacáridos/toxicidad , Ratones , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Alveolos Pulmonares/citología , Alveolos Pulmonares/fisiología , Choque Séptico/genética , Factor de Necrosis Tumoral alfa/genética
6.
Am J Respir Crit Care Med ; 187(12): 1324-34, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23611140

RESUMEN

RATIONALE: S100A12 is overexpressed during inflammation and is a marker of inflammatory disease. Furthermore, it has been ascribed to the group of damage-associated molecular pattern molecules that promote inflammation. However, the exact role of human S100A12 during early steps of immune activation and sepsis is only partially described thus far. OBJECTIVES: We analyzed the activation of human monocytes by granulocyte-derived S100A12 as a key function of early inflammatory processes and the development of sepsis. METHODS: Circulating S100A12 was determined in patients with sepsis and in healthy subjects with experimental endotoxemia. The release of human S100A12 from granulocytes as well as the promotion of inflammation by activation of human monocytes after specific receptor interaction was investigated by a series of in vitro experiments. MEASUREMENTS AND MAIN RESULTS: S100A12 rises during sepsis, and its expression and release from granulocytes is rapidly induced in vitro and in vivo by inflammatory challenge. A global gene expression analysis of S100A12-activated monocytes revealed that human S100A12 induces inflammatory gene expression. These effects are triggered by an interaction of S100A12 with Toll-like receptor 4 (TLR4). Blocking S100A12 binding to TLR4 on monocytes or TLR4 expressing cell lines (HEK-TCM) abrogates the respective inflammatory signal. On the contrary, blocking S100A12 binding to its second proposed receptor (receptor for advanced glycation end products [RAGE]) has no significant effect on inflammatory signaling in monocytes and RAGE-expressing HEK293 cells. CONCLUSIONS: Human S100A12 is an endogenous TLR4 ligand that induces monocyte activation, thereby acting as an amplifier of innate immunity during early inflammation and the development of sepsis.


Asunto(s)
Inflamación/etiología , Monocitos/fisiología , Proteínas S100/fisiología , Sepsis/inmunología , Receptor Toll-Like 4/fisiología , Adulto , Anciano , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas S100/sangre , Proteína S100A12 , Sepsis/sangre , Receptor Toll-Like 4/sangre , Adulto Joven
7.
J Immunol ; 182(7): 4349-56, 2009 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-19299735

RESUMEN

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that is expressed ubiquitously in the lungs. Engagement of RAGE leads to activation of multiple intracellular signaling pathways, including NF-kappaB and subsequent transcription of several proinflammatory mediators. To determine the role of RAGE in the innate immune response to S. pneumoniae pneumonia, RAGE-deficient (RAGE(-/-)) and wild-type mice were intranasally inoculated with S. pneumoniae. S. pneumoniae pneumonia resulted in an up-regulation of constitutively present RAGE expression in lung tissue, especially in the interalveolar septae. RAGE(-/-) mice showed an improved survival, which was accompanied by a lower bacterial load in the lungs at 16 h and a decreased dissemination of the bacteria to blood and spleen at 16 and 48 h after inoculation. RAGE(-/-) macrophages showed an improved killing capacity of S. pneumoniae in vitro. Lung inflammation was attenuated in RAGE(-/-) mice at 48 h after inoculation, as indicated by histopathology and cytokine/chemokine levels. Neutrophil migration to the lungs was mitigated in the RAGE(-/-) mice. In addition, in RAGE(-/-) mice, activation of coagulation was diminished. Additional studies examining the effect of RAGE deficiency on the early (6-h) inflammatory response to S. pneumoniae did not reveal an early accelerated or enhanced immune response. These data suggest that RAGE plays a detrimental role in the host response to S. pneumoniae pneumonia by facilitating the bacterial growth and dissemination and concurrently enhancing the pulmonary inflammatory and procoagulant response.


Asunto(s)
Neumonía Neumocócica/inmunología , Receptores Inmunológicos/inmunología , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocinas/biosíntesis , Quimiocinas/inmunología , Quimiotaxis de Leucocito/inmunología , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Neumonía Neumocócica/patología , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Streptococcus pneumoniae/crecimiento & desarrollo
8.
Crit Care Med ; 38(6): 1414-22, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20386310

RESUMEN

OBJECTIVE: The receptor for advanced glycation end products mediates a variety of inflammatory responses. Soluble receptor for advanced glycation end products has been suggested to function as a decoy abrogating cellular activation. High-mobility group box 1 is a high-affinity binding ligand for the receptor for advanced glycation end products with cytokine activities and plays a role in sepsis. DESIGN: Controlled, in vivo laboratory study. SETTING: Research laboratory of a health sciences university. SUBJECTS: C57BL/6 mice. INTERVENTIONS: Peritonitis was induced by intraperitoneal injection of Escherichia coli. Mice received soluble receptor for advanced glycation end products or anti-high-mobility group box 1 immunoglobulin G, or the appropriate control treatment. MEASUREMENTS AND MAIN RESULTS: Soluble receptor for advanced glycation end products-treated mice demonstrated an enhanced bacterial dissemination to liver and lungs, accompanied by increased hepatocellular injury and exaggerated systemic cytokine release, 20 hrs after intraperitoneal administration of Escherichia coli. Soluble receptor for advanced glycation end products administration in healthy, uninfected mice did not induce an immune response. Remarkably, lung inflammation was unaffected. Furthermore, high-mobility group box 1 release was enhanced during peritonitis and anti-high-mobility group box 1 treatment was associated with higher bacterial loads in liver and lungs. CONCLUSIONS: These data are the first to suggest that receptor for advanced glycation end products ligands, including high-mobility group box 1, limit bacterial dissemination during Gram-negative sepsis.


Asunto(s)
Infecciones por Escherichia coli/inmunología , Proteína HMGB1/fisiología , Inmunidad Innata/fisiología , Peritonitis/inmunología , Receptores Inmunológicos/inmunología , Sepsis/inmunología , Animales , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/patología , Femenino , Proteína HMGB1/administración & dosificación , Infusiones Parenterales , Ligandos , Hígado/metabolismo , Hígado/microbiología , Hígado/patología , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Peritonitis/metabolismo , Peritonitis/patología , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/administración & dosificación , Sepsis/metabolismo , Sepsis/patología
9.
Am J Pathol ; 174(6): 2182-9, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19435793

RESUMEN

Patients with respiratory failure often require supplemental oxygen therapy and mechanical ventilation. Although both supportive measures are necessary to guarantee adequate oxygen uptake, they can also cause or worsen lung inflammation and injury. Hyperoxia-induced lung injury is characterized by neutrophil infiltration into the lungs. The urokinase plasminogen activator receptor (uPAR) has been deemed important for leukocyte trafficking. To determine the expression and function of neutrophil uPAR during hyperoxia-induced lung injury, uPAR expression was determined on pulmonary neutrophils of mice exposed to hyperoxia. Hyperoxia exposure (O2>80%) for 4 days elicited a pulmonary inflammatory response as reflected by a profound rise in the number of neutrophils that were recovered from bronchoalveolar lavage fluid and lung cell suspensions, as well as increased bronchoalveolar keratinocyte-derived chemokine, interleukin-6, total protein, and alkaline phosphatase levels. In addition, hyperoxia induced the migration of uPAR-positive granulocytes into lungs from wild-type mice compared with healthy control mice (exposed to room air). uPAR deficiency was associated with diminished neutrophil influx into both lung tissues and bronchoalveolar spaces, which was accompanied by a strong reduction in lung injury. Furthermore, in uPAR(-/-) mice, activation of coagulation was diminished. These data suggest that uPAR plays a detrimental role in hyperoxia-induced lung injury and that uPAR deficiency is associated with diminished neutrophil influx into both lung tissues and bronchoalveolar spaces, accompanied by decreased pulmonary injury.


Asunto(s)
Hiperoxia/inmunología , Lesión Pulmonar/inmunología , Neutrófilos/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/biosíntesis , Animales , Western Blotting , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocinas/biosíntesis , Ensayo de Inmunoadsorción Enzimática , Femenino , Interleucina-6/biosíntesis , Lesión Pulmonar/patología , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila/inmunología , Receptores del Activador de Plasminógeno Tipo Uroquinasa/deficiencia
10.
Am J Respir Crit Care Med ; 180(11): 1098-106, 2009 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-19762566

RESUMEN

RATIONALE: Myeloid-related protein-8 (MRP8) and MRP14 can form heterodimers that elicit a variety of inflammatory responses. We showed that MRP8/14 is a ligand for Toll-like receptor-4, and that mice deficient in MRP8/14 are protected against endotoxic shock-induced lethality. OBJECTIVES: To determine (1) the extent of MRP8/14 release in patients with sepsis and/or peritonitis and in healthy humans exposed to LPS and (2) the contribution of MRP8/14 to the host response in murine abdominal sepsis. METHODS: MRP8/14 was measured in 51 patients with severe sepsis, 8 subjects after intravenous injection of LPS, and 17 patients with peritonitis. Host responses to sepsis were compared in mrp14 gene-deficient (and thereby MRP8/14-deficient) and wild-type mice intraperitoneally injected with Escherichia coli. MEASUREMENTS AND MAIN RESULTS: Patients with sepsis displayed elevated circulating MRP8/14 concentrations on both Days 0 and 3, and LPS injection resulted in systemic MRP8/14 release in healthy humans. In patients with peritonitis, MRP8/14 levels in abdominal fluid were more than 15-fold higher than in plasma. MRP14-deficient mice displayed improved defense against E. coli abdominal sepsis in an early phase, as indicated by diminished dissemination of the bacteria at 6 hours. In addition, MRP14-deficient mice demonstrated decreased systemic inflammation, as reflected by lower cytokine plasma concentrations, and less severe liver damage. CONCLUSIONS: Human sepsis and endotoxemia are associated with enhanced release of MRP8/14. In abdominal sepsis, MRP8/14 likely occurs primarily at the site of the infection, facilitating bacterial dissemination at an early phase and liver injury.


Asunto(s)
Calgranulina A/genética , Calgranulina B/genética , Expresión Génica/genética , Peritonitis/complicaciones , Sepsis/complicaciones , Sepsis/genética , Anciano , Animales , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/microbiología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Peritonitis/microbiología , Sepsis/microbiología
11.
Mol Immunol ; 45(11): 3268-77, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18384879

RESUMEN

MD-2 is the crucial cofactor of TLR4 in the detection of LPS. Here, we show that soluble MD-2 (sMD-2) circulates in plasma of healthy individuals as a polymeric protein. The total amount of sMD-2 in septic plasma was strongly elevated and contained both sMD-2 polymers and monomers, the latter representing the putative biologically active form of MD-2. Moreover, during experimental human endotoxemia, the monomeric and total sMD-2 content in plasma increased with the kinetics of an acute phase protein. The increase in sMD-2 monomers was paralleled by enhanced TLR4 costimulatory activity. The presence of functional sMD-2 during endotoxemia and sepsis was confirmed by immunodepletion. Immunohistochemistry revealed that MD-2 expression in septic patients was strongly enhanced on endothelium and multiple inflammatory cells in lung and liver. In vitro studies showed that sMD-2 release appears to be restricted to endothelial cells and dendritic cells. Release of sMD-2 by endothelial cells was strongly enhanced by LPS and TNF-alpha stimulation. Taken together, this study demonstrates the increase of both circulating polymeric and functional monomeric sMD-2 during endotoxemia and sepsis, and evidence is provided that the endothelium is involved in this process.


Asunto(s)
Células Endoteliales/metabolismo , Endotoxemia/metabolismo , Antígeno 96 de los Linfocitos/metabolismo , Sepsis/metabolismo , Adulto , Estudios de Casos y Controles , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Células Endoteliales/patología , Endotoxemia/inmunología , Femenino , Sistema Hematopoyético/citología , Sistema Hematopoyético/efectos de los fármacos , Humanos , Cinética , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Antígeno 96 de los Linfocitos/sangre , Masculino , Persona de Mediana Edad , Sepsis/sangre , Sepsis/inmunología , Solubilidad/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología
12.
Shock ; 29(4): 441-5, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18344842

RESUMEN

High-mobility group box (HMGB) 1 is a recently discovered proinflammatory mediator that contributes to acute lung injury. We determined HMGB-1 levels in bronchoalveolar lavage fluid of patients during mechanical ventilation (MV) and ventilator-associated pneumonia (VAP). Bronchoalveolar lavage fluid was obtained from patients who were ventilated for 5 h because of an elective surgical procedure ("short-term MV"; n = 40) or for several days because of respiratory failure without acute lung injury ("long-term MV"; n = 10) and from patients who developed unilateral VAP (n = 4). Ten healthy volunteers served as controls. In healthy volunteers, HMGB-1 levels were low (median, 1.6 ngmL(-1); interquartile range [IQR], 0.7-3.7 ng mL(-1)). Although HMGB-1 levels were elevated after short-term MV, differences were not statistically significant compared with healthy volunteers (1.7 ng mL(-1); IQR, 0.8-8.5 ng mL(-1), P = 0.493 vs. healthy volunteers; P = 0.250 vs. start of MV). However, HMGB-1 levels were significantly higher in "long-term" MV patients (11.7 ng mL(-1); IQR, 8.7-37.0 ng mL(-1); P < 0.0001 vs. healthy volunteers). With unilateral VAP, HMGB-1 levels from the infected lung.were 17.4 (IQR, 8.5-23.2) ng mL(-1) (P = 0.014 vs. healthy controls); these levels were not different from those measured in the contralateral noninfected lung (P = 0.625). Summarized, long-term MV is associated with increased HMGB-1 levels in contrast to "short-term" MV. In addition, HMGB-1 levels during VAP are increased compared with healthy volunteers; however, they are not different from those found in patients intubated and mechanically ventilated for a similar period of time.


Asunto(s)
Proteína HMGB1/metabolismo , Pulmón/metabolismo , Neumonía Asociada al Ventilador/metabolismo , Respiración Artificial/métodos , Adulto , Anciano , Líquido del Lavado Bronquioalveolar/química , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Pulmón/patología , Masculino , Persona de Mediana Edad , Factores de Tiempo
13.
Crit Care ; 12(1): 103, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18254937

RESUMEN

The receptor of advanced glycation endproducts (RAGE) is a multiligand receptor that upon activation causes sustained activation of multiple inflammatory pathways. Recent evidence, summarized in a review by Bopp and colleagues in this issue of Critical Care, has implicated RAGE as a potential therapeutic target in sepsis. Here, we discuss several open issues that need to be addressed before anti-RAGE strategies can enter the sepsis clinical trial arena.


Asunto(s)
Receptores Inmunológicos/antagonistas & inhibidores , Sepsis/metabolismo , Animales , Humanos , Ratones , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/fisiología , Sepsis/tratamiento farmacológico , Sepsis/microbiología
14.
Shock ; 28(5): 570-5, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17577142

RESUMEN

Ethyl pyruvate (EP) is a stable pyruvate derivative that has been shown to exert anti-inflammatory effects in various models of systemic inflammation including endotoxemia. We here sought to determine the local effects of EP, after intrapulmonary delivery, in models of lung inflammation induced by instillation via the airways of either lipopolysaccharide (LPS, a constituent of the gram-negative bacterial cell wall) or lipoteichoic acid (LTA, a component of the gram-positive bacterial cell wall). For this, we first established that EP dose dependently reduced the responsiveness of mouse MH-S alveolar macrophages and mouse MLE-15 and MLE-12 respiratory epithelial cells to stimulation with LPS or LTA in vitro. We then showed that intranasal administration of EP dose dependently inhibited tumor necrosis factor alpha release in bronchoalveolar lavage fluid of mice challenged with either LPS or LTA via the airways. Moreover, EP reduced the recruitment of neutrophils into the bronchoalveolar space after either LPS or LTA administration. These data suggest that intrapulmonary delivery of EP diminishes lung inflammation induced by LPS or LTA, at least in part by targeting alveolar macrophages and respiratory epithelial cells.


Asunto(s)
Células Epiteliales/metabolismo , Aromatizantes/farmacología , Lipopolisacáridos/toxicidad , Macrófagos Alveolares/metabolismo , Neumonía/tratamiento farmacológico , Piruvatos/farmacología , Ácidos Teicoicos/toxicidad , Animales , Líquido del Lavado Bronquioalveolar , Línea Celular , Relación Dosis-Respuesta a Droga , Células Epiteliales/patología , Femenino , Macrófagos Alveolares/patología , Ratones , Neumonía/inducido químicamente , Neumonía/metabolismo , Neumonía/patología , Factor de Necrosis Tumoral alfa/metabolismo
15.
Thromb Haemost ; 96(6): 789-93, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17139374

RESUMEN

Sepsis is characterized by a concurrent activation of inflammation and coagulation. Recently, recombinant human activated protein C was shown to decrease mortality in patients with severe sepsis presumably due to a combined anti-inflammatory and anticoagulant effect. These promising findings led to a search for other products that influence both the inflammatory and the procoagulant response to severe infection. Ethyl pyruvate (EP) was recently identified as an experimental anti-inflammatory agent during endotoxemia and sepsis. The aim of the present study was to investigate whether EP influences coagulation besides its anti-inflammatory effects. For this we investigated the effects of EP on the expression and function of tissue factor (TF), the principal initiator of coagulation activation in sepsis, in human monocytic (THP-1) cell cultures. EP dose-dependently inhibited the production of tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta by lipopolysaccharide (LPS)-stimulated THP-1 cells at mRNA and protein level, thereby confirming its anti-inflammatory properties in this in-vitro system. In addition, EP dose-dependently attenuated the increases in TF mRNA levels, TF-protein-surface expression and cell-surface-associated TF activity in LPS-stimulated THP-1 cells. These results demonstrate for the first time that EP is a compound with combined anti-inflammatory and anticoagulant effects.


Asunto(s)
Antiinflamatorios/farmacología , Anticoagulantes/farmacología , Monocitos/efectos de los fármacos , Piruvatos/farmacología , Tromboplastina/metabolismo , Coagulación Sanguínea/efectos de los fármacos , Línea Celular , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocinas CC/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Lipopolisacáridos/farmacología , Monocitos/metabolismo , ARN Mensajero/metabolismo , Tiempo de Trombina , Factor de Necrosis Tumoral alfa/metabolismo
17.
PLoS One ; 11(1): e0141000, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26824892

RESUMEN

Klebsiella species is the second most commonly isolated gram-negative organism in sepsis and a frequent causative pathogen in pneumonia. The receptor for advanced glycation end products (RAGE) is expressed on different cell types and plays a key role in diverse inflammatory responses. We here aimed to investigate the role of RAGE in the host response to Klebsiella (K.) pneumoniae pneumonia and intransally inoculated rage gene deficient (RAGE-/-) and normal wild-type (Wt) mice with K. pneumoniae. Klebsiella pneumonia resulted in an increased pulmonary expression of RAGE. Furthermore, the high-affinity RAGE ligand high mobility group box-1 was upregulated during K. pneumoniae pneumonia. RAGE deficiency impaired host defense as reflected by a worsened survival, increased bacterial outgrowth and dissemination in RAGE-/- mice. RAGE-/- neutrophils showed a diminished phagocytosing capacity of live K. pneumoniae in vitro. Relative to Wt mice, RAGE-/- mice demonstrated similar lung inflammation, and slightly elevated-if any-cytokine and chemokine levels and unchanged hepatocellular injury. In addition, RAGE-/- mice displayed an unaltered response to intranasally instilled Klebsiella lipopolysaccharide (LPS) with respect to pulmonary cell recruitment and local release of cytokines and chemokines. These data suggest that (endogenous) RAGE protects against K. pneumoniae pneumonia. Also, they demonstrate that RAGE contributes to an effective antibacterial defense during K. pneumoniae pneumonia, at least partly via its participation in the phagocytic properties of professional granulocytes. Additionally, our results indicate that RAGE is not essential for the induction of a local and systemic inflammatory response to either intact Klebsiella or Klebsiella LPS.


Asunto(s)
Infecciones por Klebsiella/metabolismo , Klebsiella pneumoniae , Pulmón/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Animales , Quimiocinas/metabolismo , Citocinas/metabolismo , Infecciones por Klebsiella/genética , Ratones , Ratones Noqueados , Receptor para Productos Finales de Glicación Avanzada/genética
18.
Shock ; 40(3): 188-94, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23846410

RESUMEN

S100A12 is highly expressed, and serum levels correlate with individual disease activity in patients with inflammatory diseases. We here sought to determine the extent of S100A12 release and its soluble high-affinity receptor for advanced glycation end products (sRAGE) in patients with severe sepsis stratified to the three most common infectious sources (lungs, abdomen, and urinary tract) and to determine S100A12 and sRAGE concentrations at the site of infection during peritonitis. Two patient populations were studied: (a) 51 patients with sepsis due to (i) peritonitis (n = 12), (ii) pneumonia (n = 29), or (iii) urinary tract infection (n = 10); and (b) 17 patients with peritonitis. In addition, eight healthy humans were studied after intravenous injection of lipopolysaccharide (4 ng/kg). Compared with healthy volunteers, patients with severe sepsis displayed increased circulating S100A12 concentrations at day 0 (591.2 ± 101.0 vs. 106.2 ± 15.6 ng/mL [control subjects], P < 0.0001) and at day 3 (637.2 ± 111.2 vs. 106.2 ± 15.6 ng/mL [control subjects], P < 0.0001). All three severe sepsis subgroups had elevated serum S100A12 concentrations at both time points (sepsis due to [i] peritonitis [393.5 ± 89.9 at day 0 and 337.9 ± 97.2 at day 3 vs. 106.2 ± 15.6 ng/mL, control subjects, P < 0.005 and P < 0.05, respectively]; [ii] pneumonia [716.9 ± 167.0 at day 0 and 787.5 ± 164.7 at day 3 vs. 106.2 ± 15.6 ng/mL, control subjects, both P < 0.0001]; and [iii] urinary tract infection [464.2 ± 115.6 at day 0 and 545.6 ± 254.9 at day 3 vs. 106.2 ± 15.6 ng/mL, control subjects, P < 0.0001 and P < 0.05, respectively]). Remarkably, patients with sepsis due to pneumonia had the highest S100A12 levels (716.9 ± 167.0 and 787.5 ± 164.7 ng/mL at days 0 and 3, respectively). S100A12 levels were not correlated to either Acute Physiology and Chronic Health Evaluation II scores (r = -0.185, P = 0.19) or Sepsis-Related Organ Failure Assessment scores (r = -0.194, P = 0.17). Intravenous lipopolysaccharide injection in healthy humans elevated systemic S100A12 levels (peak levels at 3 h of 59.6 ± 22.0 vs. 12.4 ± 3.6 ng/mL; t = 0 h, P < 0.005). In contrast to S100A12, sRAGE concentrations did not change during severe sepsis or human endotoxemia. During peritonitis, S100A12 concentrations in abdominal fluid (12945.8 ± 4142.1 ng/mL) were more than 100-fold higher than in concurrently obtained plasma (121.2 ± 80.4 ng/mL, P < 0.0005), whereas sRAGE levels in abdominal fluid (148.8 ± 36.0 pg/mL) were lower than those in plasma (648.7 ± 145.6 pg/mL, P < 0.005) and did not increase. In conclusion, in severe sepsis, S100A12 is released systemically irrespective of the primary source of infection. During abdominal sepsis, S100A12 release likely predominantly occurs at the site of infection. Concentrations of its high-affinity sRAGE do not change during infection or human endotoxemia.


Asunto(s)
Productos Finales de Glicación Avanzada/metabolismo , Proteínas S100/metabolismo , Sepsis/metabolismo , Adulto , Anciano , Endotoxemia/metabolismo , Femenino , Humanos , Masculino , Peritonitis/metabolismo , Neumonía/metabolismo , Proteína S100A12 , Adulto Joven
19.
Mol Immunol ; 52(3-4): 183-9, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22698798

RESUMEN

The development of active tuberculosis after infection with Mycobacterium tuberculosis is almost invariably associated with a persistent or transient state of relative immunodeficiency. The receptor for advanced glycation end products (RAGE) is a promiscuous receptor that is involved in pulmonary inflammation and infection. To investigate the role of RAGE in tuberculosis, we intranasally infected wild-type (Wt) and RAGE deficient (RAGE(-/-)) mice with live virulent M. tuberculosis. While lungs of uninfected Wt mice expressed RAGE, in particular on endothelium, M. tuberculosis pneumonia was associated with an enhanced pulmonary expression of RAGE. Lung inflammation was increased in RAGE(-/-) mice, as indicated by histopathology, percentage of inflamed area, lung weight and cytokine and chemokine levels. In addition, lung lymphocyte and neutrophil numbers were increased in the RAGE(-/-) mice. RAGE(-/-) mice had modestly higher mycobacterial loads in the lungs after 3 weeks but not after 6 weeks of infection. Moreover, RAGE(-/-) mice displayed more body weight loss and enhanced mortality. In summary, pulmonary RAGE expression is increased during tuberculosis. In addition, these data suggest that RAGE plays a beneficial role in the host response to pulmonary tuberculosis.


Asunto(s)
Receptores Inmunológicos/fisiología , Tuberculosis Pulmonar/inmunología , Animales , Carga Bacteriana , Quimiocinas/biosíntesis , Citocinas/biosíntesis , Recuento de Leucocitos , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium tuberculosis/patogenicidad , Neutrófilos/inmunología , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/biosíntesis , Receptores Inmunológicos/genética , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patología
20.
Contrib Microbiol ; 17: 125-136, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21659750

RESUMEN

Sepsis is a very heterogeneous clinical syndrome broadly defined as the systemic host response to an infection. Until recently, the concept that mortality is the consequence of an uncontrolled hyperinflammatory response of the host was widely accepted. However, although some patients may die rapidly from septic shock accompanied by an overwhelming systemic inflammatory response syndrome triggered by a highly virulent pathogen, most patients survive the initial phase of sepsis, showing multiple organ failure days or weeks later. These patients often demonstrate signs of immune suppression rather than enhanced inflammation. As such, sepsis is now considered a misbalance between proinflammatory reactions (designed to kill invading pathogens but at the same time responsible for tissue damage) and anti-inflammatory responses (designed to limit excessive inflammation, but at the same time making the host more vulnerable for secondary infections). This chapter discusses key components of the pro- and anti-inflammatory response to sepsis and the regulation thereof.


Asunto(s)
Tolerancia Inmunológica , Sepsis/inmunología , Sepsis/patología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/patología , Humanos , Insuficiencia Multiorgánica , Sepsis/complicaciones
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