While it has been long known that patients with sepsis often have thrombocytopenia and that septic patients with severe thrombocytopenia have a poor prognosis and higher mortality, the role of platelets in the pathogenesis of sepsis is poorly understood. Here we report a protective role of platelets in septic shock. We show that experimental thrombocytopenia by intraperitoneal injection of an anti-glycoprotein Ibα monoclonal antibody increases mortality and aggravates organ failure whereas transfusion of platelets reduces mortality in Lipopolysaccharide-induced endotoxemia and a bacterial infusion mouse sepsis model. Plasma concentrations of proinflammatory cytokines TNF-α and IL-6 are elevated by thrombocytopenia and decreased by platelet transfusion in septic mice. Furthermore, we identify that platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the COX1/PGE2/EP4 dependent pathway. Thus, these findings demonstrate a previously unappreciated role for platelets in septic shock and suggest that platelet transfusion may be effective in treating severe septic patients.

BackgroundMesenchymal stem cells (MSCs) hold great promise for the treatment of difficult diseases. As MSCs represent a rare cell population, ex vivo expansion of MSCs is indispensable to obtain sufficient amounts of cells for therapies and tissue engineering. However, spontaneous differentiation and aging of MSCs occur during expansion and the molecular mechanisms involved have been poorly understood.Methodology/Principal FindingsHuman MSCs in early and late passages were examined for their expression of genes involved in osteogenesis to determine their spontaneous differentiation towards osteoblasts in vitro, and of genes involved in self-renewal and proliferation for multipotent differentiation potential. In parallel, promoter DNA methylation and hostone H3 acetylation levels were determined. We found that MSCs underwent aging and spontaneous osteogenic differentiation upon regular culture expansion, with progressive downregulation of TERT and upregulation of osteogenic genes such as Runx2 and ALP. Meanwhile, the expression of genes associated with stem cell self-renewal such as Oct4 and Sox2 declined markedly. Notably, the altered expression of these genes were closely associated with epigenetic dysregulation of histone H3 acetylation in K9 and K14, but not with methylation of CpG islands in the promoter regions of most of these genes. bFGF promoted MSC proliferation and suppressed its spontaneous osteogenic differentiation, with corresponding changes in histone H3 acetylation in TERT, Oct4, Sox2, Runx2 and ALP genes.Conclusions/SignificanceOur results indicate that histone H3 acetylation, which can be modulated by extrinsic signals, plays a key role in regulating MSC aging and differentiation.

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Sepsis is a leading cause of death that is characterized by uncontrolled inflammatory response. In this study, we report that scavenger receptor BI (SR-BI), a high density lipoprotein receptor, is a critical survival factor of sepsis. We induced sepsis using an established septic animal model, cecal ligation and puncture (CLP). CLP induced 100% fatality in SR-BI-null mice but only 21% fatality in wild type littermates. SR-BI-null mice exhibited aberrant inflammatory responses with delayed inflammatory cytokine generation at the early stage of sepsis and highly elevated inflammatory cytokine production 20 h after CLP treatment. To understand the mechanisms underlying SR-BI protection, we elucidated the effect of macrophage SR-BI on inflammatory cytokine generation. Macrophages from SR-BI-null mice produced significantly higher levels of inflammatory cytokines than those of wild type controls in response to LPS. Importantly, transgenic mice overexpressing SR-BI were more resistant to CLP-induced septic death. Using an HEKBlue TM cell system, we demonstrated that expression of SR-BI suppressed TLR4-mediated NF-B activation. To understand why SR-BI-null mice had a delayed inflammatory response, we elucidated the effect of SR-BI on LPS clearance during sepsis. Compared with wild type controls, SR-BI-null mice had lower plasma LPS levels in the early stage of sepsis and elevated plasma LPS levels 20 h following CLP treatment. In conclusion, our findings demonstrate that SR-BI is a critical protective modulator of sepsis in mice. SR-BI exerts its protective function through its role in modulating inflammatory response in macrophages and facilitating LPS recruitment and clearance.Sepsis is one of the major causes of death that claims over 215,000 lives and costs $16.7 billion per year in America alone (1-4). The death rate from sepsis is high, exceeding 50%, due to poor understanding of the disease (5). Identifying molecules involved in sepsis, especially endogenous protective modulators, is of great importance not only in understanding the mechanisms but also in providing new insights for efficient therapies.Scavenger receptor BI (SR-BI 2 or Scarb1) is a 75-kDa membrane protein expressed in the liver, endothelial cells, macrophages, and steroidogenic tissues (6, 7). It is a well established high density lipoprotein (HDL) receptor. It mediates intracellular uptake of cholesterol ester from HDL, which plays a key role in regulating plasma cholesterol levels and steroidogenesis (8 -11). Mice deficient in SR-BI have a 2-fold increase in plasma cholesterol levels and develop cardiovascular diseases (10,(12)(13)(14)(15)(16). Recent studies reveal that SR-BI is a multifunctional protein. It activates endothelial nitric-oxide synthase in endothelial cells in the presence of HDL (17-20), induces apoptosis in the absence of HDL/endothelial nitric-oxide synthase (21), and protects against nitric oxide (NO)-induced oxidative damage (22). Emerging evidence indicates that specific expression of SR-BI in macrophages provides protecti...