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Treatment of Experimental Candida Sepsis with a Janus Kinase Inhibitor Controls Inflammation and Prolongs Survival.
Tsirigotis, P; Papanikolaou, N; Elefanti, A; Konstantinou, P; Gkirkas, K; Rontogianni, D; Siafakas, N; Karakitsos, P; Roilides, E; Dimitriadis, G; Zerva, L; Meletiadis, J.
Afiliação
  • Tsirigotis P; Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  • Papanikolaou N; Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  • Elefanti A; Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  • Konstantinou P; Department of Pathology, Evaggelismos General Hospital, Athens, Greece.
  • Gkirkas K; Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  • Rontogianni D; Department of Pathology, Evaggelismos General Hospital, Athens, Greece.
  • Siafakas N; Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  • Karakitsos P; Department of Cytopathology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  • Roilides E; Infectious Diseases Unit, Third Department of Pediatrics, Aristotle University School of Medicine, Hippokration Hospital, Thessaloniki, Greece.
  • Dimitriadis G; Second Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  • Zerva L; Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
  • Meletiadis J; Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece jmeletiadis@med.uoa.gr.
Antimicrob Agents Chemother ; 59(12): 7367-73, 2015 Dec.
Article em En | MEDLINE | ID: mdl-26369979
Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) levels and IL-10/TNF-α ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-α ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirazóis / Candida albicans / Sepse / Inibidores de Proteínas Quinases / Janus Quinases / Candidemia / Antifúngicos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirazóis / Candida albicans / Sepse / Inibidores de Proteínas Quinases / Janus Quinases / Candidemia / Antifúngicos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2015 Tipo de documento: Article