Authors:
Shirley H.J. Mei, Jack J. Haitsma, Claudia C. Dos Santos, Yupu Deng, Patrick F.H. Lai, Arthur S. Slutsky, W. Conrad Liles, and Duncan J. Stewart
Summary:
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 & Measurements - 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 (BAL) fluid and tissues were collected for analyses. Longer term studies were performed with antibiotic co-administration to assess the effect of MSCs on survival.
Main Results - MSC treatment significantly reduced mortality in septic mice receiving appropriate antimicrobial therapy. MSCs alone significantly reduced systemic and pulmonary cytokine levels in mice with CLP-induced sepsis, preventing acute lung injury and organ dysfunction. Microarray data highlighted an overall down-regulation of inflammation and inflammation-related genes (such as IL-10, IL-6), and a shift towards 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 the efficacy of MSC therapy for experimental sepsis, and suggest that immunomodulatory cell therapy may be an effective adjunctive treatment to reduce sepsis-related morbidity and mortality.
Source:
American Journal of Respiratory & Critical Care Medicine; (06/17/10)