title: Targeting myeloid differentiation 2 for treatment of sepsis.
abstract: Sepsis continues to be a leading cause of intensive care unit (ICU) death. Gram-negative bacteria are among the most important pathogens of sepsis and their LPS content is regarded to be an important stimulator that elicits the systemic inflammatory reaction. MD-2 is a small secreted glycoprotein that can bind to both the hydrophobic portion of LPS and to the extracellular domain of TLR4. The interaction between MD-2 and LPS bridges the two TLR4 molecules and induces the dimerization of LPS-MD-2-TLR4, which forms the structural basis for biological functions of TLR4/MD-2 complex. Due to its essential role in mediating the interaction between LPS and TLR4, MD-2 has been extensively explored as a therapeutic target for treatment of inflammatory disorders such as sepsis. Eritoran is a synthetic tetraacylated lipid A that binds directly to MD-2 and antagonizes LPS binding to the same site. Although eritoran showed positive results in phase I and phase II clinical trials of severe sepsis, a phase III clinical study for severe sepsis has failed. More effective therapeutic strategies are in need to treat this devastating clinical disorder.
authors.affiliation: Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Guangjie
authors.initials: G
authors.lastname: Duan
authors.affiliation: Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yousheng
authors.initials: Y
authors.lastname: Liu
mesh_terms: D004187:Disaccharides / Q000627:therapeutic use*; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods*; D011485:Protein Binding / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013403:Sugar Phosphates / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004187:Disaccharides; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D013403:Sugar Phosphates; D051197:Toll-Like Receptor 4; C512420:eritoran