The Roles of Myeloid Derived Suppressor Cells in Sepsis.

Literature has demonstrated the severity of sepsis, vascular permeability changes through the blood vessels, causing multiple organ failure and even death! I havealso demonstrated that septic patients with high extravascular lung water index (EVLWI) could cause a high vascular permeability, multi-organs dysfunction and death from my previous published articles! Some researchers have begun to explore the role of myeloid derived suppressor cell (MDSC) in sepsis. However, the role of MDSC in sepsis has been not yet well studies and concluded. Our research team has found and published that two subtypes of MDSCs in lung cancer patients: granulocytic MDSC and monocytic MDSC, which could reflect the treatment response and prognosis of lung cancer! This study is designed to isolate subtypes of MDSCs from septic patients, explore the correlation of MDSC and vascular permeability in sepsis. From our preliminary data, we found that both subtypes of MDSCs increased in septic patients. Interestingly, patients with high EVLWI had more monocytic MDSC, meanwhile patients with low EVLWI had more granulocytic MDSC! According to our preliminary data, we hypothesized that granulocytic MDSC, which may secret some factors (X factors) to improve endothelial permeability, oxygenation and organ perfusion. Meanwhile, these cells and factors could reverse the effects of endothelial barrier disruption from sepsis cascades and monocytic MDSC. Finally, it caused the patients to recovery from sepsis and survival! The first year we will work to explore correlation of 2 subtypes MDSCs and EVLWI, cytokines (IL-6, TNF-α, IL-8) and vascular permeability factor (e.g., VEGF, VEGFR, thrombin, thrombomodulin, angiopoietin, MMP, etc.), and sepsis prognosis in septic patients. By increasing the study numbers, and reproducible data, we will recognize the phenomenon of our preliminary data. The second year we will explore an endothelial cell model in vitro. 2 subtypes MDSCs from septic patients, and serum from patients with different EVLWI will be added to the endothelial cells to observe the morphologic and permeability changes of endothelial cells. As well as the downstream signal transduction of endothelial cells will also be explored. We will use HUVECs Culture and Treatment, Measurement of endothelial permeability in vitro, Immunocytochemistry and confocal laser scanning microscopy and Western blot methods. Quantitative immunoassay and fluorescence microscopy to explore conjugate destroy endothelial cell binding molecules and endothelial cells and vascular permeability. In the third year, we will try to find out the x factor by proteomics to prove our hypothesis. Further more, the X factor will be validated to reverse vascular permeability of endothelial cells from the model in vitro. At the same time, its downstream signaling of endothelial cells will be also studied via ELISA, immunostaning, and confocal microscope with fluorescence! Bone marrow-derived progenitor cells (BMPC) could prevent thrombin-induced increase in lung vascular permeability. Therefore, thrombin pathway could be x factor between MDSC and endothelial cells permeability. From the study, we could understand the impacts of subtypes of MDSC on the endothelial cells and the prognosis of septic patients. The novel treatments of sepsis may be developed from the study!

Project ID:PC10408-2549
External Project ID:MOST104-2314-B182-049