Endothelial inflammatory pathways and dysfunction in sepsis and injury

The human body contains more than one trillion endothelial cells, which are uniquely situated to sense and respond to invading pathogens. Microvascular endothelial cells play a substantial role in the pathophysiology of sepsis and injuries such as ischemia reperfusion injury. Endothelial dysfunction contributes to vascular leak, coagulopathy, shock, and organ injury during acute inflammation. We described the broad endothelial effects of TLR2 activation, showing that direct activation of TLR2 expressed by human lung microvascular endothelial cells (HMVEC) upregulates their production of cytokines, chemokines, and coagulation intermediaries, promotes neutrophil-HMVEC adhesion, and increases HMVEC permeability. Consistent with these in vitro effects, we found that bacterial lipopeptide causes coagulopathy and vascular leak in mice. These data suggest that the activation of endothelial TLR2 may contribute to outcomes of sepsis, such as multiple organ failure. Our recent work points to substantial differences in TLR signaling between endothelial cells and leukocytes, and also differences in the signaling pathways leading to TLR-dependent permeability versus cytokine production. We observe that ERK1/2 inhibition augments IL-6 production by HMVEC, but it reduces IL-6 production by monocytes. Furthermore, we have found that despite augmenting LPS-induced IL-6production, ERK1/2 inhibition reduces LPS-induced permeability of HMVEC. Similarly, NF-κB inhibition or siRNA knock down reduces cytokine production, but they do not affect HMVEC permeability induced by TLR2 and TLR4 agonists. These findings raise the possibility of developing therapies that preferentially target specific responses in sepsis and injury.