NOS2 and Sepsis: TMD1 structure within the thrombin–TM complex could specifically degrade HMGB1 to a less pro-inflammatory form that block its interaction with RAGE, while rTMD1 interfere with LPS-CD14 binding and inhibit subsequent LPS-induced inflammation via suppressing the MAPK and NF-κB signaling pathway as well as iNOS expression in macrophages.303,304 In animal models, recombinant TM significantly reduce LPS-induced sepsis mortality characterized with reduced levels of TNF-α and inflammatory cell infiltration in the lungs and livers.303,305