Project Summary Lipopolysaccharide (LPS), also known as endotoxin, is a component of Gram-negative bacteria’s outer membrane. LPS induces an inflammatory response, severe endotoxin septic shock. Sepsis poses a serious public health problem, with an overall mortality rate of 25-50%. Vascular peroxidase-1 (VPO1), which is identified by the PI’s group, is new member of animal heme-containing peroxidase family. VPO1 is unique in the family. It possesses five leucine-rich repeats and four immunoglobulin domains in addition to the peroxidase domain. VPO1 is highly expressed in cardiovascular system and the lung, and is secreted into blood, which is approximate 1000-fold higher than myeloperoxidase in plasma. VPO1 also exists in bronchoalveolar lavage fluid at relatively higher concentration. Our data show that VPO1 specifically interacts with LPS via its LRRs and Ig domains. Interestingly, administration of LPS or Gram-negative bacteria causes more severe inflammatory response in VPO1-deficient mice than in wild-type mice. We hypothesize that VPO1 mediates resistance to LPS-mediated inflammatory response and septic shock by inhibiting the interaction of LPS and TLR4/MD- 2/CD14 co-receptor. The specific aim of the proposal is to extensively evaluate VPO1 roles in LPS-mediated inflammatory response and septic shock. The in vitro and in vivo methods including using VPO1-deficient mice will be carried out. Identification and characterization of VPO1 role in protection from systemic inflammatory response and endotoxin shock will advance new knowledge of innate immunity and inflammatory responses, which will ultimately lead to the development of novel therapeutic strategies for endotoxin shock.