The Role of Circulating Fibrocyte and Endothelial Injury in Sepsis Induced Organ Failure

Sepsis-induced endothelial injury plays a critical role in mediating the illness progression to multiple organ failure and patients’ mortality. Fibrocytes are mesenchymal progenitors involved in normal and pathologic repair. Bronchoalveoalr lavage (BAL) fibrocyte percentage is significantly increased in patients with acute lung injury (ALI) and is associated with increased mortality. Fibrocytes play an important role in endothelial cell apoptosis and proliferation in wound healing process. But the role of fibrocytes in mediating sepsis associated endothelial cell proliferation or endothelial injury has never been investigated. Four-and-a-half LIM-only protein 2 (FHL2) plays an important role in lipopolysaccharide (LPS)-induced inflammatory response. In muscle cells, FHL2 enhances production of proinflammatory cytokines through activation of NF-kB and p38 signaling pathways. The preliminary results demonstrated a depressed degree of lung injury in FHL2 knockout (FHL2-/-) mice compared with WT mice that received 4-hr i.p. LPS challenge. In addition, circulating fibrocyte numbers are increased in the acute phase of LPS response in WT mice received i.p. LPS challenge but not in in FHL2-/- mice. Therefore, the aims of this study are 1. To compare the difference in sepsis induced inflammatory responses and organ injury in WT and FHL2-/- mice. 2. To measure the induction of circulating fibrocytes and recruitment of fibrocytes to the lung, liver, and kidney after i.p. LPS-induced sepsis. 3. To investigate the role of endothelial injury in sepsis-induced organ injury in WT and FHL2-/- mice. 4. To evaluate the effects of fibrocytes on sepsis-induced endothelial cell injury and organ failure. In the first year, the study will measure the induction of circulating fibrocytes and recruitment of fibrocytes to the lung, liver, and kidney in WT and FHL2-/- mice receiving i.p. LPS challenge for 4 hr. The study will measure organ injury, neutrophil sequestration and endothelial permeability in the sepsis mice model. The production of proinflammatory cytokines, activation of MAP kinase signaling pathways and NF-kB will also be measured in FHL2-/- and WT mice with sepsis. In the second year, the study will use AMD3100, an antagonist for CXCR4, for blockade of CXCL12-CXCR4 axis. The study will measure the number of circulating fibrocytes and recruitment of fibrocytes to the lung, liver, and kidney after LPS-induced sepsis in mice with and without CXCR4 blockade. The degree of sepsis-induced organ failure and endothelial injury will be determined. In summary, our study will elucidate the mechanism for decreased organ injury, inflammatory response, and endothelial injury in FHL2-/- mice. The effects of fibrocyte in mediating endothelial injury and subsequent organ failure will be clearly delineated. With all the information from this project, a better understanding of the role of fibrocyte and FHL2 in sepsis will be achieved which may provide benefits in the development for possible target in future treatment of sepsis.

Project ID:PC10308-1271
External Project ID:MOST103-2314-B182-054-MY2