Postulated role of TM in modulating response to endotoxin/sepsis. LPS from gram-negative bacteria bind to the coreceptor CD14 of monocytes (not depicted) and endothelial cells, triggering proinflammatory intracellular signaling pathways via activation of the TLR4-MD2 complex. In the early stages of infection/inflammation (A), when the endothelium is unperturbed and in a quiescent state, TM interferes with LPS-CD14 interactions in 2 ways: (1) the lectin-like domain of TM binds to LPS via Le^y, and (2) the serine-threonine–rich region of TM binds to CD14. Both would predictably block LPS-CD14 interactions, thereby interfering with the proinflammatory response. As the balance tips, and inflammation persists and progresses, the endothelial cells become inflamed and activated (B). TM expression decreases, soluble fragments of TM are released via proteolysis (only some of which are represented), and the TM-dependent protective mechanisms on the endothelium are reduced or lost. Expression of adhesion molecules and Le^y on the endothelial cells increase (not depicted), activated leukocytes adhere (Figure 2), and the inflammatory response escalates. Again, therapeutic recombinant TM comprising the entire ectodomain, or the lectin-like domain alone, or the EGF-like region plus the serine-threonine–rich region (TMD23) will likely be of benefit, in part, by blocking LPS-CD14 interactions. LLD, lectin-like domain.