Hepatic venoocclusive disease (HVOD) of the liver is the second most common cause of death in autologous transplantation and the third most common cause of death in allogeneic bone marrow transplantation. Disruption of the hepatic circulation is a dominant feature. In late HVOD this is attributed to sinusoidal fibrosis and fibrotic venoocclusion, but the cause of circulatory disruption in early HVOD is unknown. The goal of this application is to examine the mechanisms involved in the circulatory disruption of early HVOD.
The specific aims of this proposal are: 1) to examine in vitro whether drug-induced injury alters production of vasoactive mediators by liver cells (sinusoidal endothelial cells (SEC), Kupffer cells, stellate cells and hepatocytes); studies will examine drug-induced changes in release of nitric oxide, eicosanoids, and endothelin-1, in enzyme activity and expression of protein and MRNA of ecNOS (nitric oxide synthase), INOS, COX1 (cyclooxygenase) and COX-2. 2) To use light and electron microscopy, immunohistochemistry and in vivo microscopy to characterize the changes in an in vivo model of HVOD and examine the role of inflammation, nitric oxide, eicosanoids, and endothelin-1 using antibodies, inhibitors and agonists. The ultimate goal is to understand the mechanisms involved in drug-induced HVOD, so that therapeutic strategies can be developed.
