Oxidative Stress and Hepatic Stellate Cells: A PARADOXICAL RELATIONSHIP

Abstract

In physiology, reactive oxygen species (ROS) are produced by most cells for normal function and as a defense mechanism against foreign particles, microbes and viruses. Hepatic macrophages (Kupffer cells), sinusoidal endothelial cells, hepatocytes and hepatic stellate cells (HSCs) are all capable of generating ROS in physiology and pathology. ROS are also produced by infiltrating inflammatory cells during acute and chronic liver injury. Increased levels of ROS have been implicated in apoptotic/necrotic death of hepatocytes, and liver failure. In contrast to causing injury to hepatocytes, ROS and lipid peroxidation products induce transdifferentiation of the quiescent HSCs into an activated highly proliferative myofibroblast-like phenotype. ROS and lipid peroxidation products also stimulate the synthesis of extracellular matrix (ECM) by activated HSCs. Deposition of excessive amounts of ECM is the primary mechanism of fibrosis and cirrhosis of the liver, and interactions between ROS and HSCs appear to play a major role in this pathology. Although these findings suggest that HSCs are resistant to the injurious actions of ROS, there is compelling evidence demonstrating ROS-induced death of activated HSCs. Detailed mechanistic understanding of such paradoxical interactions between ROS and HSCs will be critical for developing therapies for chronic fibrotic liver disease.

Keywords: apoptosis; fibrosis; free radicals; liver; stellate cells.

Figure 1. Localization of hepatic stellate cell

The cartoon depicts localization of a hepatic stellate cell (HSC) in the space of Disse, adjacent to hepatocytes. Note that the cytosolic extensions cover hepatocytes on either side, penetrate the fenestrations (EF) in sinusoidal endothelial cells (SEC), and also traverse the hepatocyte plate and contact HSC in the neighboring perisinusoidal space. KC, Kupffer cell.

Figure 2. Apoptosis of culture-activated HSCs by superoxide

Rat HSCs were cultured and used in passage 3. After the cells had achieved semiconfluence, they were subjected to superoxide challenge (1 mM hypoxanthine + 2 mU/ml xanthine oxidase). Control cells were incubated in the presence of hypoxanthine alone. After 24 hours, photomicrograph was taken. Note that superoxide-challenged cells have shrunk, and several have already undergone apoptosis. Magnification ×100.

Figure 3. A schema showing the effects of ROS and other mediators on HSCs during liver injury

Upon liver injury (e.g., CCl₄ administration), Kupffer cells, platelets and infiltrating blood cells such as monocytes and neutrophils produce several mediators including ROS and lipid peroxides. CCl₄ also causes hepatocyte apoptosis/necrosis, which release several mediators, including ROS and lipid peroxides. These mediators act on quiescent HSCs, which release retinoids and change their phenotype to myofibroblast-like cells. While these mediators continue to induce HSC activation, and also proliferation of activated HSCs and promote their fibrogenic activity, a subpopulation can undergo apoptosis in response to ROS challenge. NFkB, c-Myb, PI3K and ERK1/2 have been shown to participate in activation/proliferation of HSCs. See text for details.