CELLULAR AND MOLECULAR-BIOLOGY OF THE INFLAMED LIVER

Inflammation of the hepatic parenchyma is primarily the result of cyto kine-mediated activation of sinusoidal cells, their expression of leuk ocyte adhesion molecules, further local release of proinflammatory cyt okines, and recruitment of exogenous leukocytes. The Kupffer cell play s a key role in promoting parenchymal inflammation. Sinusoidal endothe lial cells, perisinusoidal stellate (Ito) cells, and pit cells (reside nt natural killer cells) contribute to the proinflammatory microenviro nment, and hepatocytes themselves express adhesion molecules and relea se proinflammatory cytokines. Exogenous leukocytes, especially neutrop hils, T lymphocytes, and circulating macrophages, marginate, adhere to the sinusoidal endothelium, and may enter the parenchymal space. They release additional proinflammatory cytokines and noxious reactive che mical species, creating an injurious local environment. The particular victims are hepatocytes. Cytokine stimulation of the hepatocellular a cute phase response commandeers the hepatocyte metabolic machinery, an d there is severe disruption of hepatocellular bile formation leading to cholestasis. Moreover, cytokine-stimulated hepatocyte apoptosis may ensue, and microvascular occlusion may engender more extensive ischem ic hepatocellular necrosis. Counteracting downregulatory mechanisms ha ve been documented but are minimal in both number and apparent impact. Many of these insights have been gained using experimental models of sepsis and endotoxemia, and such models are highlighted in this review .