Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration.
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.
Laboratório De Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, RJ, Brazil.
Mariana G A
MG
Teixeira-da-Cunha
Rachel N
RN
Gomes
Nathassia
N
Roehrs
Fernando A
FA
Bozza
Stephen M
SM
Prescott
Diana
D
Stafforini
Guy A
GA
Zimmerman
Patricia T
PT
Bozza
Hugo C
HC
Castro-Faria-Neto
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000008:administration & dosage*; D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D010529:Peritoneal Cavity / Q000382:microbiology; D011994:Recombinant Proteins / Q000008:administration & dosage; D012480:Salmonella Infections / Q000188:drug therapy / Q000382:microbiology; D012486:Salmonella typhimurium; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology*
D018932:Chemokine CCL2; D011994:Recombinant Proteins; D009569:Nitric Oxide; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase