A PPARγ AGONIST ENHANCES BACTERIAL CLEARANCE THROUGH... : Shock (original) (raw)

Basic Science Aspects

A PPARγ AGONIST ENHANCES BACTERIAL CLEARANCE THROUGH NEUTROPHIL EXTRACELLULAR TRAP FORMATION AND IMPROVES SURVIVAL IN SEPSIS

Araújo, Cláudia V.; Campbell, Clarissa; Gonçalves-de-Albuquerque, Cassiano F.; Molinaro, Raphael; Cody, Mark J.; Yost, Christian C.; Bozza, Patricia T.; Zimmerman, Guy A.; Weyrich, Andrew S.; Castro-Faria-Neto, Hugo C.; Silva, Adriana R.

*Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil

†Department of Internal Medicine

‡Department of Pediatrics

§Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah

Address reprint requests to Adriana R. Silva, Av. Brasil, 4365, Manguinhos, Rio de janeiro, RJ Brazil, 21040-900. E-mail: [email protected]

Received 7 July, 2015

Revised 23 July, 2015

Accepted 16 October, 2015

This work was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil), PAPES-FIOCRUZ, PRONEX (MCT, Brazil), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brazil), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil), and National Institutes of Health (NIH), USA.

The authors report no conflicts of interest.

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Abstract

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.