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1.
J Infect Dis ; 211(6): 995-1003, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25305323

ABSTRACT

BACKGROUND: Severe gram-negative bacterial infections and sepsis are major causes of morbidity and mortality. Dysregulated, excessive proinflammatory cytokine expression contributes to the pathogenesis of sepsis. A CD28 mimetic peptide (AB103; previously known as p2TA) that attenuates CD28 signaling and T-helper type 1 cytokine responses was tested for its ability to increase survival in models of polymicrobial infection and gram-negative sepsis. METHODS: Mice received AB103, followed by an injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS); underwent induction E. coli 018:K1 peritonitis induction, followed by treatment with AB103; or underwent cecal ligation and puncture (CLP), followed by treatment with AB103. The effects of AB103 on factors associated with and the lethality of challenge infections were analyzed. RESULTS: AB103 strongly attenuated induction of tumor necrosis factor α and interleukin 6 (IL-6) by LPS in human peripheral blood mononuclear cells. Receipt of AB103 following intraperitoneal injection of LPS resulted in survival among 73% of CD1 mice (11 of 15), compared with 20% of controls (3 of 15). Suboptimal doses of antibiotic alone protected 20% of mice (1 of 5) from E. coli peritonitis, whereas 100% (15 of 15) survived when AB103 was added 4 hours following infection. Survival among mice treated with AB103 12 hours after CLP was 100% (8 of 8), compared with 17% among untreated mice (1 of 6). In addition, receipt of AB103 12 hours after CLP attenuated inflammatory cytokine responses and neutrophil influx into tissues and promoted bacterial clearance. Receipt of AB103 24 hours after CLP still protected 63% of mice (5 of 8). CONCLUSIONS: Single-dose AB103 reduces mortality in experimental models of polymicrobial and gram-negative bacterial infection and sepsis, warranting further studies of this agent in clinical trials.


Subject(s)
Anti-Bacterial Agents/therapeutic use , CD28 Antigens/chemistry , Escherichia coli Infections/prevention & control , Peritonitis/prevention & control , Sepsis/prevention & control , Animals , Animals, Outbred Strains , Anti-Bacterial Agents/pharmacology , CD28 Antigens/therapeutic use , Cells, Cultured , Chemokines/metabolism , Escherichia coli Infections/drug therapy , Female , Humans , Lipopolysaccharides/pharmacology , Mice, Inbred BALB C , Molecular Mimicry , Neutrophil Infiltration/drug effects , Peritonitis/drug therapy , Peritonitis/immunology , Protein Interaction Domains and Motifs , Sepsis/drug therapy
2.
Antimicrob Agents Chemother ; 58(6): 3276-84, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24687492

ABSTRACT

It has been previously shown that mice subjected to an aerosol exposure to Yersinia pestis and treated with ß-lactam antibiotics after a delay of 42 h died at an accelerated rate compared to controls. It was hypothesized that endotoxin release in antibiotic-treated mice accounted for the accelerated death rate in the mice exposed to aerosol Y. pestis. Imipenem, a ß-lactam antibiotic, binds to penicillin binding protein 2 with the highest affinity and produces rounded cells. The binding of imipenem causes cells to lyse quickly and thereby to release less free endotoxin. Two imipenem regimens producing fractions of time that the concentration of free, unbound drug was above the MIC (fT>MIC) of approximately 25% (6/24 h) and 40% (9.5/24 h) were evaluated. In the postexposure prophylaxis study, the 40% and 25% regimens produced 90% and 40% survivorship, respectively. In the 42-h treatment study, both regimens demonstrated a 40 to 50% survivorship at therapy cessation and some deaths thereafter, resulting in a 30% survivorship. As this was an improvement over the results with other ß-lactams, a comparison of both endotoxin and cytokine levels in mice treated with imipenem and ceftazidime (a ß-lactam previously demonstrated to accelerate death in mice during treatment) was performed and supported the original hypotheses; however, the levels observed in animals treated with ciprofloxacin (included as an unrelated antibiotic that is also bactericidal but should cause little lysis due to a different mode of action) were elevated and significantly (7-fold) higher than those with ceftazidime.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Imipenem/therapeutic use , Plague/prevention & control , Yersinia pestis/drug effects , Aerosols , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Ceftazidime/pharmacokinetics , Ceftazidime/pharmacology , Ceftazidime/therapeutic use , Ciprofloxacin/pharmacokinetics , Ciprofloxacin/pharmacology , Ciprofloxacin/therapeutic use , Cytokines/metabolism , Endotoxins/analysis , Female , Imipenem/pharmacokinetics , Imipenem/pharmacology , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Plague/metabolism , Plague/microbiology , Survival Analysis
3.
Shock ; 35(5): 492-8, 2011 May.
Article in English | MEDLINE | ID: mdl-21263385

ABSTRACT

The RAGE (receptor for advanced glycation end products) is believed to play a role in sepsis by perpetuating inflammation. The interaction of RAGE with a variety of host-derived ligands that accumulate during stress and inflammation further induces the expression of RAGE. It was previously shown that a rat anti-RAGE monoclonal antibody protected mice from lethality in a cecal ligation and puncture model. We studied the effects of a humanized anti-RAGE monoclonal antibody in the murine pneumococcal pneumonia model of sepsis. Moreover, a gene expression analysis was performed in lung tissue of animals that underwent cecal ligation and puncture and treated with the rat anti-RAGE monoclonal antibody, compared with controls. Administration of humanized anti-RAGE mAb 6 h after intratracheal infection with Streptococcus pneumoniae improved mortality in BALB/c mice whether a 7.5 mg/kg (P < 0.01) or a 15 mg/kg dose (P < 0.01) was administered in combination with antibiotics. Gene expression analysis showed that many of the genes modulated by treatment with the anti-RAGE antibody were those that play an important role in regulating inflammation. Anti-RAGE monoclonal antibody offered a survival advantage to septic mice. This protective role in treated animals is supported by the observed gene expression profile changes of genes involved in sepsis and inflammation.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Pneumonia, Pneumococcal/drug therapy , Pneumonia, Pneumococcal/metabolism , Receptors, Immunologic/immunology , Sepsis/drug therapy , Sepsis/metabolism , Animals , Antibodies, Monoclonal/therapeutic use , Disease Models, Animal , Female , Kaplan-Meier Estimate , Male , Mice , Mice, Inbred BALB C , Pneumonia, Pneumococcal/microbiology , Receptor for Advanced Glycation End Products , Sepsis/microbiology , Streptococcus pneumoniae/pathogenicity
4.
J Infect Dis ; 201(8): 1250-7, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20205571

ABSTRACT

BACKGROUND: Nonsteroidal agonists have been developed that selectively bind to and activate estrogen receptor beta (ERbeta) rather than estrogen receptor alpha (ERalpha). ERbeta is expressed equally in both male and female mammals in multiple extragonadal tissues. Work reported elsewhere has demonstrated that ERbeta agonists have beneficial effects in multiple (but not all) models of inflammatory diseases and also increase survival in experimentally induced sepsis. METHODS: In these experiments, ERbeta agonists (ERB-041 or WAY-202196) were compared with vehicle control in the murine cecal ligation and puncture (CLP) model and in the pneumococcal pneumonia model of sepsis. The effect of WAY-202196 on the gene expression profile in the CLP model was further studied by transcriptome analysis of lung and small intestine tissue samples. RESULTS: ERbeta agonists provided a significant survival benefit in both experimental models of bacterial sepsis. This survival advantage was accompanied by reduced histologic evidence of tissue damage, reduced transcription of multiple proinflammatory proteins by transcriptome analysis and was not associated with increased bacterial outgrowth. CONCLUSIONS: ERbeta agonist administration provided a survival advantage in septic animals and appears to be a promising therapeutic modality in sepsis.


Subject(s)
Estrogen Receptor beta/agonists , Naphthols/therapeutic use , Oxazoles/therapeutic use , Sepsis/drug therapy , Animals , Disease Models, Animal , Estrogen Receptor beta/biosynthesis , Estrogen Receptor beta/physiology , Female , Gene Expression Profiling , Male , Mice , Mice, Inbred BALB C , Pneumonia, Pneumococcal/drug therapy , Sepsis/physiopathology , Transcription, Genetic/drug effects
5.
Crit Care Med ; 34(8): 2188-93, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16755255

ABSTRACT

OBJECTIVE: To determine the effect of an estrogen receptor-beta selective agent in experimental models of systemic infection and sepsis. DESIGN: WAY-202196, a nonsteroidal selective estrogen receptor-beta agonist, was tested in the murine listeriosis model, the neutropenic rat Pseudomonas aeruginosa infection, and the mouse cecal ligation and puncture sepsis models. SETTING: University-affiliated biomedical research laboratory. SUBJECTS: BALB/c mice and Sprague-Dawley rats. INTERVENTIONS: WAY-202196 or control (vehicle) was administered orally in doses ranging from 1.5 to 50 mg/kg at various time points in the three experimental model systems. MEASUREMENTS AND MAIN RESULTS: Susceptibility of mice treated with a single oral dose of up to 50 mg/kg WAY-202196 did not differ from those treated with vehicle alone after systemic challenge by Listeria monocytogenes, suggesting a lack of generalized immunosuppression. In the neutropenic rat model, daily administration of WAY-202196 (50 mg/kg) significantly increased survival against an otherwise lethal challenge of P. aeruginosa 12.4.4 compared with the control group (83% vs. 25% survival; p < 0.05). Preservation of intestinal mucosal weight and prevention of histopathologic changes were also observed with the administration of WAY-202196. Similar results were obtained in a cecal ligation and puncture model, in which multiple oral doses of WAY-202196 (50 mg/kg) improved survival (83% vs. 0%; p < 0.05), preserved intestinal epithelial integrity, and significantly reduced systemic bacteremia and peritoneal interleukin-6 and tumor necrosis factor levels. The estrogen receptor-beta agonist provided a comparable level of protection in both male and female animals. CONCLUSION: These results indicate that oral administration of WAY-202196 preserved gastrointestinal barrier function and improved outcome in experimental models of systemic infection and inflammation. WAY-202196 and similar agents may prove useful clinically as a novel treatment strategy for the treatment or prevention of severe sepsis.


Subject(s)
Naphthols/pharmacology , Shock, Septic/drug therapy , Administration, Oral , Animals , Ascitic Fluid/metabolism , Bacteremia/drug therapy , Bacteremia/microbiology , Disease Models, Animal , Estrogen Receptor beta/agonists , Female , Interleukin-6/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/ultrastructure , Listeria monocytogenes , Male , Mice , Mice, Inbred BALB C , Neutropenia/complications , Pseudomonas Infections/drug therapy , Rats , Rats, Sprague-Dawley , Shock, Septic/microbiology , Tumor Necrosis Factor-alpha/metabolism
6.
J Infect Dis ; 192(12): 2074-80, 2005 Dec 15.
Article in English | MEDLINE | ID: mdl-16288370

ABSTRACT

BACKGROUND: An experimental vaccine for sepsis, composed of detoxified Escherichia coli J5 lipopolysaccharide (LPS) complexed with the outer membrane protein (OMP) of Neisseria meningitidis group B, induces anti-core glycolipid antibody and has been tested in pilot studies in human volunteers. METHODS: Mice were immunized with the LPS-J5/OMP vaccine with or without synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs as a vaccine adjuvant (CpG ODN). The efficacy of the vaccine-induced antibody response was tested in a cecal ligation and puncture model. RESULTS: Immunization resulted in a >20-fold increase in anti-core glycolipid antibody levels, which were further increased 5-fold by the addition of CpG ODN, compared with the levels in mice in the control group. The vaccine provided a survival advantage after a cecal ligation and puncture was performed (P < .01) and significantly decreased the levels of bacteria in organs. Immunoglobulin G (IgG) anti-core glycolipid antibodies were decreased in mice to a significantly greater extent than were levels of total circulating IgG or IgG to the OMP part of the vaccine complex, suggesting specific epitope binding and clearance. CONCLUSIONS: These results indicate that the detoxified LPS-J5/OMP vaccine induces high levels of antibody against the core glycolipid of LPS and functions in vivo to promote clearance of gram-negative bacteria and improve the outcome of experimental polymicrobial intra-abdominal sepsis.


Subject(s)
Bacterial Outer Membrane Proteins/immunology , Endotoxins/immunology , Gram-Negative Bacterial Infections/prevention & control , Oligodeoxyribonucleotides/immunology , Sepsis/prevention & control , Vaccination/methods , Vaccines , Adjuvants, Immunologic/administration & dosage , Animals , Antibodies, Bacterial/blood , Bacterial Outer Membrane Proteins/administration & dosage , Disease Models, Animal , Endotoxins/administration & dosage , Escherichia coli/immunology , Glycolipids/immunology , Immunoglobulin G/blood , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/immunology , Liver/microbiology , Mice , Mice, Inbred BALB C , Neisseria meningitidis/immunology , Oligodeoxyribonucleotides/administration & dosage , Spleen/microbiology , Survival Analysis
7.
J Infect Dis ; 190(9): 1655-60, 2004 Nov 01.
Article in English | MEDLINE | ID: mdl-15478072

ABSTRACT

The intentional release of anthrax in the United States in 2001 resulted in 11 cases of inhalational disease, with an attendant mortality rate of 45%. Current therapeutic options for anthrax are limited; antimicrobials target only replicating organisms, thus allowing bacterial toxins to cause unchecked, devastating physiological derangements in the host. Novel approaches that target the cytotoxic effects of anthrax exotoxins are needed. Chloroquine (CQ), a commonly used antimalarial agent, endows anthrax-intoxicated murine peritoneal macrophages with a 50% and 35% marginal survival advantage at 2 and 4 h, respectively, over that of untreated control cells. The cell rescue is dose dependent and, at lower concentrations, results in delayed cell death. We subsequently studied the effect of CQ in BALB/c mice challenged with anthrax lethal toxin. CQ-treated mice demonstrated reduced tissue injury, as assessed by histopathological examination of the spleen and by peripheral blood differential cell count ratios. CQ significantly enhanced survival and may augment current treatment and prophylaxis options for this otherwise lethal infection.


Subject(s)
Anthrax/drug therapy , Antigens, Bacterial/toxicity , Bacillus anthracis/pathogenicity , Bacterial Toxins/toxicity , Chloroquine/pharmacology , Chloroquine/therapeutic use , Animals , Anthrax/microbiology , Anthrax/pathology , Bacillus anthracis/drug effects , Cell Death/drug effects , Cell Survival/drug effects , Cells, Cultured , Chloroquine/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Leukocyte Count , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/drug effects , Mice , Mice, Inbred BALB C , Monocytes , Neutrophils , Specific Pathogen-Free Organisms , Spleen/pathology , Survival Analysis
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