Apoptosis signal-regulating kinase 1-mediated signaling pathway regulates lipopolysaccharide-induced tissue factor expression in pulmonary microvasculature.

Sepsis remains a life-threatening event and acute lung injury (ALI) is one of the complications induced by it. ALI is characterized by fibrin deposition, an indication of local activation of the coagulation cascade. Tissue factor (TF) expressed in the microvasculature acts as a critical initiator of blood coagulation in ALI. Lipopolysaccharide (LPS), a component of the outer envelope of all Gram-negative bacteria, is a highly proinflammatory molecule that elicits a wide range of endothelial responses, including the upregulation of TF; however, the molecular mechanism in LPS-induced TF expression in the pulmonary microvasculature has not been determined. We analyzed the role of apoptosis signal-regulating kinase (ASK1), an upstream kinase of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK), in order to clarify the signaling molecule regulating LPS-induced TF expression. The results showed the following: 1) LPS induces hTF mRNA expression in normal human lung microvascular endothelial cells (HMVEC-L); 2) LPS induces ASK1 phosphorylation in HMVEC-L; 3) LPS-induced TF mRNA expression is depressed in the dominant negative form of ASK1 stably-transfected porcine artery endothelial (PAE) cells; 4) LPS stimulation induces p38 MAPK and JNK phosphorylations in HMVEC-L; 5) LPS-induced p38 MAPK and JNK phosphorylations are depressed in the dominant negative form of ASK1 stably-transfected PAE cells; and 6) SB 203580 as a specific inhibitor of p38 MAPK, but not SP 600125 as a specific inhibitor of JNK cascade, attenuates LPS-induced hTF mRNA expression. These results indicate that the ASK1-p38 MAPK cascade may regulate LPS-induced TF expression in pulmonary microvasculature. (c) 2010 Elsevier B.V. All rights reserved.