Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 182, Issue 8, Pages 1047-1057Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201001-0010OC
Keywords
mesenchymal stem cells; sepsis; multiple organ dysfunction syndrome; acute lung injury; cell therapy
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Funding
- Canadian Institutes of Health Research [MOP-74752, MOP-8558, MOP-69042]
- Northern Therapeutics (Toronto, Canada)
- NSERC
- Ontario Graduate Scholarship
- Weston Foundation
- McLaughlin Centre for Molecular Medicine
- Canada Research Chair in Infectious Diseases and Inflammation
- Northern Therapeutics Inc
- Asthmatx
- Broncus
- Lilly
- NIH
- CIHR
- Northern Therapeutics
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Rationale: 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. Objectives: 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 C57BI/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. Measurements and Main 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.
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