The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Gabriela C Fernandez - One of the best experts on this subject based on the ideXlab platform.
-
tolerance to lipopolysaccharide promotes an enhanced neutrophil extracellular traps formation leading to a more efficient Bacterial Clearance in mice
Clinical and Experimental Immunology, 2012Co-Authors: Veronica I Landoni, Paula Chiarella, Daiana Martiregreco, Pablo Schierloh, N Vanrooijen, Barbara Rearte, Marina S Palermo, Martin A Isturiz, Gabriela C FernandezAbstract:Tolerance to lipopolysaccharide (LPS) constitutes a stress adaptation, in which a primary contact with LPS results in a minimal response when a second exposure with the same stimulus occurs. However, active important defence mechanisms are mounted during the tolerant state. Our aim was to assess the contribution of polymorphonuclear neutrophils (PMN) in the Clearance of Bacterial infection in a mouse model of tolerance to LPS. After tolerance was developed, we investigated in vivo different mechanisms of Bacterial Clearance. The elimination of a locally induced polymicrobial challenge was more efficient in tolerant mice both in the presence or absence of local macrophages. This was related to a higher number of PMN migrating to the infectious site as a result of an increased number of PMN from the marginal pool with higher chemotactic capacity, not because of differences in their phagocytic activity or reactive species production. In vivo, neutrophils extracellular trap (NET) destruction by nuclease treatment abolished the observed increased Clearance in tolerant but not in control mice. In line with this finding, in vitro NETs formation was higher in PMN from tolerant animals. These results indicate that the higher chemotactic response from an increased PMN marginal pool and the NETs enhanced forming capacity are the main mechanisms mediating Bacterial Clearance in tolerant mice. To sum up, far from being a lack of response, tolerance to LPS causes PMN priming effects which favour distant and local anti-infectious responses.
Timothy R Billiar - One of the best experts on this subject based on the ideXlab platform.
-
lipopolysaccharide Clearance Bacterial Clearance and systemic inflammatory responses are regulated by cell type specific functions of tlr4 during sepsis
Journal of Immunology, 2013Co-Authors: Meihong Deng, Melanie J Scott, Patricia Loughran, Gregory A Gibson, Chhinder P Sodhi, Simon C Watkins, David J Hackam, Timothy R BilliarAbstract:The morbidity associated with Bacterial sepsis is the result of host immune responses to pathogens, which are dependent on pathogen recognition by pattern recognition receptors, such as TLR4. TLR4 is expressed on a range of cell types, yet the mechanisms by which cell-specific functions of TLR4 lead to an integrated sepsis response are poorly understood. To address this, we generated mice in which TLR4 was specifically deleted from myeloid cells (LysMTLR4KO) or hepatocytes (HCTLR4KO) and then determined survival, Bacterial counts, host inflammatory responses, and organ injury in a model of cecal ligation and puncture (CLP), with or without antibiotics. LysM-TLR4 was required for phagocytosis and efficient Bacterial Clearance in the absence of antibiotics. Survival, the magnitude of the systemic and local inflammatory responses, and liver damage were associated with Bacterial levels. HCTLR4 was required for efficient LPS Clearance from the circulation, and deletion of HCTLR4 was associated with enhanced macrophage phagocytosis, lower Bacterial levels, and improved survival in CLP without antibiotics. Antibiotic administration during CLP revealed an important role for hepatocyte LPS Clearance in limiting sepsis-induced inflammation and organ injury. Our work defines cell type–selective roles for TLR4 in coordinating complex immune responses to Bacterial sepsis and suggests that future strategies for modulating microbial molecule recognition should account for varying roles of pattern recognition receptors in multiple cell populations.
Hugo C Castrofarianeto - One of the best experts on this subject based on the ideXlab platform.
-
a pparγ agonist enhances Bacterial Clearance through neutrophil extracellular trap formation and improves survival in sepsis
Shock, 2015Co-Authors: Claudia V Araujo, Guy A Zimmerman, Patricia T Bozza, Clarissa Campbell, Cassiano Felippe Goncalvesdealbuquerque, Raphael Molinaro, Mark J Cody, Christian C Yost, Andrew S Weyrich, Hugo C CastrofarianetoAbstract:Dysregulation of the inflammatory response against infection contributes to mortality in sepsis. Inflammation provides critical host defense, but it can cause tissue damage, multiple organ failure, and death. Because the nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ) exhibits therapeutic potential, we characterized the role of PPARγ in sepsis. We analyzed severity of clinical signs, survival rates, cytokine production, leukocyte influx, and Bacterial Clearance in a cecal ligation and puncture (CLP) model of sepsis in Swiss mice. The PPARγ agonist rosiglitazone treatment improved clinical status and mortality, while increasing IL-10 production and decreasing TNF-α and IL-6 levels, and peritoneal neutrophil accumulation 24 h after CLP. We noted increased Bacterial killing in rosiglitazone treated mice, correlated with increased generation of reactive oxygen species. Polymorphonuclear leukocytes (PMN) incubated with LPS or Escherichia coli and rosiglitazone increased peritoneal neutrophil extracellular trap (NET)-mediated Bacterial killing, an effect reversed by the PPARγ antagonist (GW 9662) treatment. Rosiglitazone also enhanced the release of histones by PMN, a surrogate marker of NET formation, effect abolished by GW 9662. Rosiglitazone modulated the inflammatory response and increased Bacterial Clearance through PPARγ activation and NET formation, combining immunomodulatory and host-dependent anti-Bacterial effects and, therefore, warrants further study as a potential therapeutic agent in sepsis.
-
Bacterial Clearance is improved in septic mice by platelet activating factor acetylhydrolase paf ah administration
PLOS ONE, 2013Co-Authors: Mariana G A Teixeiradacunha, Rachel N Gomes, Nathassia Roehrs, Fernando A Bozza, Stephen M Prescott, Diana M Stafforini, Guy A Zimmerman, Patricia T Bozza, Hugo C CastrofarianetoAbstract:Current evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis. Strategies to block inflammatory mediators such as PAF have been investigated as adjuvant therapies for sepsis. PAF-AH, the enzyme responsible for PAF degradation, showed positive results in pre-clinical studies and phase II clinical trials, but the results of a phase III study were disappointing. In this study, we investigated the potential protective mechanism of PAF-AH in sepsis using the murine model of cecal ligation and puncture (CLP). Treatment with rPAF-AH increased peritoneal fluid levels of the anti-inflammatory mediators MCP-1/CCL2 after CLP. The numbers of bacteria (CFU) in the peritoneal cavity were decreased in the rPAF-AH-treated group, indicating more efficient Bacterial Clearance after rPAF-AH treatment. Interestingly, we observed increased levels of nitric oxide (NO) after PAF-AH administration, and rPAF-AH treatment did not decrease CFU numbers either in iNOS-deficient mice or in CCR2-deficient mice. We concluded that administration of exogenous rPAF-AH reduced inflammatory injury, altered cytokine levels and favored Bacterial Clearance with a clear impact on mortality through modulation of MCP-1/CCL2 and NO levels in a clinically relevant sepsis model.
-
Bacterial Clearance in septic mice is modulated by mcp 1 ccl2 and nitric oxide
Shock, 2013Co-Authors: Rachel N Gomes, Fernando A Bozza, Guy A Zimmerman, Patricia T Bozza, Mariana G A Teixeiracunha, Rodrigo T Figueiredo, Patricia E Almeida, Silvio Caetano Alves, Marcelo T Bozza, Hugo C CastrofarianetoAbstract:Bacterial Clearance is one of the most important beneficial consequences of the innate immune response. Chemokines are important mediators controlling leukocyte trafficking and activation, whereas reactive oxygen and nitrogen species are effectors in Bacterial killing. In the present work, we used in vivo and in vitro models of infections to study the role of monocyte chemoattractant protein 1 (MCP-1)/CCL2 and nitric oxide (NO) in the Bacterial Clearance in sepsis. Our results show that MCP-1/CCL2 and NO levels are increased in the peritoneal cavity of mice 6 h after sepsis induced by cecal ligation and puncture. Pretreatment with anti-MCP-1/CCL2 monoclonal antibodies increased the number of colony-forming units (CFUs) recovered in the peritoneal lavage fluid. Moreover, CFU counts were increased in the peritoneal fluid of CCR2 mice subjected to cecal ligation and puncture. In vitro stimulation of peritoneal macrophages with recombinant MCP-1/CCL2 reduced CFU counts in the supernatant after challenge with Escherichia coli. Conversely, treatment with anti-MCP-1/CCL2 increased CFU counts under the same experimental condition. Stimulation of cultured macrophages with MCP-1/CCL2 and interferon had a synergistic effect on NO production. Macrophages from CCL2 mice showed a consistent decrease in NO production when compared with wild-type controls after stimulation with LPS + interferon. Finally, we showed incubation of macrophages with E. coli, and the ERK inhibitor U0126 increased CFU numbers and decreased intracellular levels of NO. In conclusion, we demonstrated for the first time that MCP-1/CCL2 has a crucial role in the Clearance of bacteria by mechanisms involving increased expression of inducible NO synthase and production of NO by ERK signaling pathways.
Zenaide M N Quezado - One of the best experts on this subject based on the ideXlab platform.
-
disruption of the transient receptor potential vanilloid 1 can affect survival Bacterial Clearance and cytokine gene expression during murine sepsis
Anesthesiology, 2011Co-Authors: Virginia Guptill, Xizhong Cui, Alfia Khaibullina, Jason M Keller, Nicholas Spornick, Andrew J Mannes, Michael J Iadarola, Zenaide M N QuezadoAbstract:Background: Previous studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel has a role in sepsis, but it is unclear whether its effect on survival and immune response is beneficial or harmful. Methods: We studied the effects of genetic (Trpv1-knockout vs. wild-type [WT] mice) and pharmacologic disruption of TRPV1 with resiniferatoxin (an agonist) or capsazepine (an antagonist) on mortality, Bacterial Clearance, and cytokine expression during lipopolysaccharide or cecal ligation and puncture—induced sepsis. Results: After cecal ligation and puncture, genetic disruption of TRPV1 in Trpv1-knockout versus WT mice was associated with increased mortality risk (hazard ratio, 2.17; 95% CI, 1.23―3.81; P = 0.01). Furthermore, pharmacologic disruption of TRPV1 with intrathecal resiniferatoxin, compared with vehicle, increased mortality risk (hazard ratio, 1.80; 95% CI, 1.05―3.2; P = 0.03) in WT, but not in Trpv1-knockout, mice. After lipopolysaccharide, neither genetic (Trpv1 knockout) nor pharmacologic disruption of TRPV1 with resiniferatoxin had significant effect on survival compared with respective controls. In contrast, after lipopolysaccharide, pharmacologic disruption of TRPV1 with capsazepine, compared with vehicle, increased mortality risk (hazard ratio, 1.92; 95% CI, 1.02―3.61; P = 0.04) in WT animals. Furthermore, after cecal ligation and puncture, increased mortality in resiniferatoxin-treated WT animals was associated with higher blood Bacterial count (P = 0.0004) and higher nitrate/nitrite concentrations and down-regulation of tumor necrosis factor α expression (P = 0.004) compared with controls. Conclusions: Genetic or pharmacologic disruption of TRPV1 can affect mortality, blood bacteria Clearance, and cytokine response in sepsis in patterns that may vary according to the sepsis-inducing event and the method of TRPV1 disruption.
David J Hackam - One of the best experts on this subject based on the ideXlab platform.
-
lipopolysaccharide Clearance Bacterial Clearance and systemic inflammatory responses are regulated by cell type specific functions of tlr4 during sepsis
Journal of Immunology, 2013Co-Authors: Meihong Deng, Melanie J Scott, Patricia Loughran, Gregory A Gibson, Chhinder P Sodhi, Simon C Watkins, David J Hackam, Timothy R BilliarAbstract:The morbidity associated with Bacterial sepsis is the result of host immune responses to pathogens, which are dependent on pathogen recognition by pattern recognition receptors, such as TLR4. TLR4 is expressed on a range of cell types, yet the mechanisms by which cell-specific functions of TLR4 lead to an integrated sepsis response are poorly understood. To address this, we generated mice in which TLR4 was specifically deleted from myeloid cells (LysMTLR4KO) or hepatocytes (HCTLR4KO) and then determined survival, Bacterial counts, host inflammatory responses, and organ injury in a model of cecal ligation and puncture (CLP), with or without antibiotics. LysM-TLR4 was required for phagocytosis and efficient Bacterial Clearance in the absence of antibiotics. Survival, the magnitude of the systemic and local inflammatory responses, and liver damage were associated with Bacterial levels. HCTLR4 was required for efficient LPS Clearance from the circulation, and deletion of HCTLR4 was associated with enhanced macrophage phagocytosis, lower Bacterial levels, and improved survival in CLP without antibiotics. Antibiotic administration during CLP revealed an important role for hepatocyte LPS Clearance in limiting sepsis-induced inflammation and organ injury. Our work defines cell type–selective roles for TLR4 in coordinating complex immune responses to Bacterial sepsis and suggests that future strategies for modulating microbial molecule recognition should account for varying roles of pattern recognition receptors in multiple cell populations.