RESUMO
Using an actual infection model of Pseudomonas aeruginosa sepsis in neutropenic rats, the potential utility of a combination anticytokine approach for the treatment of sepsis was tested. A dimeric tumor necrosis factor binding protein (TNF-BP) consisting of two soluble recombinant human TNF type 1 receptors linked with polyethylene glycol was used with recombinant human interleukin-1 receptor antagonist (IL-1ra). Despite having levels of bacteremia and endotoxemia similar to the control group (survivors, 0/18), 30% of IL-1ra-treated animals survived (P < .05); 31% of TNF-BP-treated animals survived (P < .01). Unexpectedly, the combination of IL-1ra plus TNF-BP proved to be uniformly fatal (survivors, 0/20). Endotoxin (P < .0001) and bacteremia (P < .01) levels were >10-fold higher than levels in animals treated with IL-1ra alone, TNF-BP alone, or placebo. Disseminated microabscesses in major organs were found in animals treated with combination immunotherapy. Combination anticytokine therapy may exacerbate systemic infection and worsen outcome in experimental sepsis.
Assuntos
Proteínas de Transporte/efeitos adversos , Infecções por Pseudomonas/terapia , Receptores do Fator de Necrose Tumoral , Choque Séptico/terapia , Sialoglicoproteínas/efeitos adversos , Animais , Bacteriemia/sangue , Proteínas de Transporte/química , Proteínas de Transporte/uso terapêutico , Contagem de Colônia Microbiana , Ciclofosfamida/farmacologia , Quimioterapia Combinada , Endotoxinas/sangue , Humanos , Imunossupressores/farmacologia , Imunoterapia/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1 , Neutropenia/induzido quimicamente , Polietilenoglicóis/química , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Ratos , Receptores Tipo I de Fatores de Necrose Tumoral , Proteínas Recombinantes/efeitos adversos , Choque Séptico/patologia , Sialoglicoproteínas/uso terapêutico , Receptores Chamariz do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/análiseRESUMO
A chimeric protein consisting of the N-terminal domain of lipopolysaccharide-binding protein and the C-terminal domain of bactericidal/permeability-increasing protein demonstrated a dose-dependent survival benefit (P = 0.001) and reduced endotoxin levels (P < 0.01) in neutropenic rats with Pseudomonas aeruginosa sepsis. This lipopolysaccharide-binding protein-bactericidal/ permeability-increasing peptide has favorable pharmacokinetics and antiendotoxin properties which may be of value for human sepsis.
