16.1Introduction

The retinal pigment epithelium is a single layer of pigmented cells located between the photoreceptors of the neurosensory retina and the choroid. Retinal pigment epithelial (RPE) cells provide multiple important functions essential to the maintenance of overlaying photoreceptors and therefore visual function [1].

Aerobic organisms require molecular oxygen for vital cellular processes. As a consequence of respiration and enzymatic activities, electrons can be transferred to molecular oxygen to form oxygen radicals known collectively as reactive oxygen species (ROS). ROS formed in this manner include superoxide anion, hydrogen peroxide (H2O2), and hydroxyl radical. There is another form of ROS, known as singlet oxygen, which is formed through energy transfer from the light activation of a natural endogenous photosensitizer (i.e., porphyrin) to molecular oxygen. All ROS are cytotoxic, including H2O2 which is a mild oxidant, but in the presence of metal catalysts, H2O2 can be converted to hydroxyl radicals, which are highly cytotoxic and can cause cell death. The production of ROS in excess of the endogenous cellular capacity for their detoxification and utilization results in nonhomeostatic states referred to as oxidative stress [2].

Low levels of ROS may modulate physiological functions via various signal pathways [2–7]. High levels of ROS can modify or oxidize cellular components (DNA, protein, lipids, and carbohydrates), and these changes lead to loss of cell function or cell death [2–7]. There are two major types of cell death: apoptosis and necrosis. High levels of ROS can induce apoptosis, while extremely high levels of ROS cause necrosis [2, 8–11].

There are endogenous antioxidants present in the cell, which can defend against the deleterious effects of ROS, including various antioxidant compounds (i.e., vitamin C, vitamin E, reduced thiol glutathione, etc.) and enzyme systems that can quench ROS [2].

Oxidative stress, which involves the presence of excessive ROS, has been implicated in the aging process, in tumorigenesis, and in the occurrence of various other diseases, including neurodegenerative diseases, cardiovascular diseases, inflammatory or autoimmune diseases, etc. [2–7].

In the eye, RPE cells are particularly susceptible to damage from oxidative stress. The RPE is located between the neurosensory retina and the choroid, and is therefore exposed to a highly oxidative environment due to the high partial pressure of oxygen diffusing from the underlying choriocapillaries [12–15]. One of the important functions of RPE cells is the phagocytosis and digestion of shed photoreceptor outer segments. The process of RPE phagocytosis results in the generation of endogenous ROS [16, 17] due to the fact that shed outer segments are extremely rich in polyunsaturated fatty acids. ROS oxidation of retinal polyunsaturated fatty acids initiates a chain reaction producing an additional abundance of lipid peroxide ROS. Additionally, RPE cells accumulate lipofuscin (an end product of phagocytosis of outer segments), a photosensitizer. Upon exposure of lipofuscin to short blue visible light (430 nm), ROS including superoxide and singlet oxygen are generated. All of these factors cause RPE cells to be in a constant state of high oxidative stress [12–15].

Oxidative stress can cause multiple changes in the RPE by several mechanisms. ROS at low levels may influence RPE function through various signaling pathways [18–20]. For example, in our laboratory, we found that H2O2 at nontoxic levels induces the production of interleukin-6 (a proinflammatory cytokine) in cultured human RPE via the activation of the p38 MAPK pathway [18]. ROS at high levels may induce apoptosis of RPE cells [21–35]. Loss of RPE cells leads to loss to the overlying photoreceptors and decreased visual function. Oxidative damage of RPE cells has been implicated in the pathogenesis of certain eye diseases, such as the age-related macular degeneration (AMD) [12–15]. AMD is a progressive deterioration of the macular region in the retina. The macula is the central area of the retina which is responsible for fixation and the ability to see fine details. AMD is the leading cause of blindness in aged persons in developed countries. The prevalence of AMD in Americans 40 years of age or older is 1.5%, and it has been estimated that 1.75 million persons suffer from this disease in the USA [36].

The search for substances which can protect RPE cells from oxidative stress is an area which has elicited substantial interest [21–23, 25, 27–29, 31, 32]. Hepatocyte growth factor (HGF) is a pleiotropic growth factor that when bound to its receptor (mesenchymal–epithelial transition factor [MET]) activates several signal pathways and promotes migration, mitosis, and survival of various cells [37–43]. It has been reported that HGF has a protective effect on several cell types against oxidative stress, tested mainly in in vitro models using H2O2 as the oxidative stressor [44–50]. RPE cells both produce HGF and express the HGF receptors [51, 52]. HGF stimulates mitosis, migration, and morphological changes of RPE cells [50–58]. In the