title: Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis.
abstract: BACKGROUND
  Sepsis refers to the clinical syndrome of severe systemic inflammation precipitated by infection. Despite appropriate antimicrobial therapy, sepsis-related morbidity and mortality remain intractable problems in critically ill patients. Moreover, there is no specific treatment strategy for the syndrome of sepsis-induced multiple organ dysfunction.
  
  
  OBJECTIVE
  We hypothesized that mesenchymal stem cells (MSCs), which have been shown to have immunomodulatory properties, would reduce sepsis-induced inflammation and improve survival in a polymicrobial model of sepsis.
  
  
  METHODS
  Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture (CLP), followed 6 hours later by an intravenous injection of MSCs or saline. Twenty-eight hours after CLP, plasma, bronchoalveolar lavage fluid and tissues were collected for analyses. Longer-term studies were performed with antibiotic coadministration to assess the effect of MSCs on survival.
  
  
  RESULTS
  MSC treatment significantly reduced mortality in septic mice receiving appropriate antimicrobial therapy. MSCs alone reduced systemic and pulmonary cytokine levels in mice with CLP-induced sepsis, preventing acute lung injury and organ dysfunction, despite the low levels of cell persistence. Microarray data highlighted an overall down-regulation of inflammation and inflammation-related genes (such as IL-10, IL-6) and a shift toward up-regulation of genes involved in promoting phagocytosis and bacterial killing. Finally, bacterial clearance was significantly greater in MSC-treated mice, in part due to enhanced phagocytotic activity of the host immune cells.
  
  
  CONCLUSIONS
  These data demonstrate that MSCs have beneficial effects on experimental sepsis, possibly by paracrine mechanisms, and suggest that immunomodulatory cell therapy may be an effective adjunctive treatment to reduce sepsis-related morbidity and mortality.
authors.affiliation: The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada, K1H 8L6.
authors.forename: Shirley H J
authors.initials: SH
authors.lastname: Mei
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Haitsma
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Dos Santos
authors.forename: Yupu
authors.initials: Y
authors.lastname: Deng
authors.forename: Patrick F H
authors.initials: PF
authors.lastname: Lai
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D003131:Combined Modality Therapy; D005260:Female; D005786:Gene Expression Regulation; D056747:Immunomodulation; D007249:Inflammation / Q000235:genetics / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents