Role of the MAPK in the monocyte/macrophage procoagulant response, implications for fulminant viral hepatitis

grantor: University of TorontoViral fulminant hepatic failure (FHF) is one of the most devastating diseases in clinical medicine, with progression from complete health to death occurring in a matter of days or weeks. Liver destruction is characterized by the dense infiltration of monocuclear cells (monocytes, macrophages and lymphocytes) with subsequent activation of the inflammatory coagulation cascade. We have studied the activation of the coagulation cascade by cells of the monocyte/macrophage lineage under conditions that model the integrin-dependent migration of the cells across the vascular endothelium and into the liver parenchyma, and the reaction of the cells to a viral pathogen known to induce FHF in mice. Tissue factor (TF), one of the chief inducers of coagulation, is expressed on monocytic cells in response to surface integrin crosslinking and following transendothelial migration. Fig-2/fibroleukin, a potent prothrombinase, is expressed on macrophages after infection with Murine Hepatitis Virus Strain-3 (MHV-3). Recent work has suggested that Mitogen Activated Protein Kinases (MAPK) are involved in integrin signaling and the monocyte response to infectious stimuli. We postulated that the ERK and p38 MAPK play critical roles in monocyte migration and the reaction of macrophages to MHV-3. We demonstrated activation of the ERK and p38 MAPK in response to integrin crosslinking, monocyte adhesion to activated endothelial beds, and infection of macrophages with MHV-3. Taking advantage of novel, selective inhibitors of the ERK MAPK pathway and the p38 MAPK (PD98059 and SB203580, respectively) We found that both MAPK modules are essential for the induction of TF in the adhesion dependent response to monocyte transendothelial migration. The p38 MAPK was necessary for fgl-2 expression in response to MHV-3; ERK was necessary for fgl-2 activity. These studies suggest that critical aspects of the monocyte/macrophage response which drives liver destruction in viral FHF are under the control of the ERK and p38 MAPK. Thus, the selective inhibition of these modules may be of use in attenuating the inflammatory damage of viral FHF.Ph.D