Catálogo de publicaciones - libros

The densely cellular retina with its intricate arrangement of neurons requires highly specialized circulations to meet its demanding metabolic requirements without compromising its extracellular space, which is a highly defined microenvironment conducive to neurotransmission, phototransduction and the complex interaction of metabolites, growth factors and vasoactive agents. The retinal circulation, which supplies the inner retina, is observed ophthalmoscopically as a regular geometrically arranged network of vessels and their three-dimensional complexity reflects the cellular density of the retinal neuropile. The caliber of directly viewed vessels is determined by the size of the red cell column, as the vessel walls and peripheral plasma layer are virtually transparent. The vessels accordingly appear wider during fluorescein angiography as dye mixes with the luminal plasma. As the vessel walls sclerose with age, stress or disease processes they become visible, due to reflected light on ophthalmoscopy, and obscure the red cell column to varying degrees. Abnormalities of the retinal circulation are key pointers to retinal dysfunction and disease and frequently highlight perturbations of the systemic circulation, e.g., diabetes, hypertension, and sickle cell disease.

The circulatory system evolved so that nutrients and chemicals required for cellular function can be efficiently transferred from central organs to the extremities. Because of its importance to the growth and survival of other tissues, the circulatory system forms during early stages of development, and its correct development and early function is absolutely critical for survival of the embryo. During development, blood vessel formation occurs by three processes, the initial formation of vessels from yolk sacs during early embryogenesis, and by the distinct processes of vasculogenesis and angiogenesis during subsequent development [ 33 , 35 ].

The vasculature is the first organ to arise during development. Blood vessels run through virtually every organ in the body, ensuring metabolic homeostasis by supplying oxygen and nutrients and removing waste products. Consequently, a dysfunction of blood vessels compromises normal organ performance. This in turn may lead to congenital or acquired diseases, disability or even death. The lymphatic system develops in parallel but secondary to the blood vascular system. It serves an essential function in absorbing and transporting tissue fluid and extravasated proteins and cells back to the venous circulation. Understanding the principles of how blood and lymph vessels form and which angiogenic factors are involved might provide novel attractive opportunities for treatment of angiogenic disorders.

Neovascular diseases of the eye include retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), and the exudative or “wet” form of age-related macular degeneration (ARMD). Together these diseases affect all age groups and are the leading causes of vision impairment in developed nations [ 77 ].

In the past few decades, our knowledge of the mechanisms underlying retinal vasoproliferation has increased greatly (see Chapters 2, 3.1, 3.2 and 3.3). While vasoproliferation was once considered to be mainly a consequence of ischemia, current evidence also supports a contribution of inflammatory mechanisms. Inflammation is also highly related to vascular leakage in diseases that are known to result in retinal and macular edema. Recently, inflammatory mechanisms have gained interest with respect to the retinal pathology following ischemia, as well as in diseases such as diabetic retinopathy (DR) and sickle cell retinopathy (see Chapter 27.1). In this chapter, the discussion will focus on the published data relating to the inflammatory mechanisms in ischemic retinal diseases such as DR. The definition of inflammation in this setting is the involvement of any leukocyte-mediated pathology in the course of the disease.

Much of the effort to understand diabetic retinopathy has focused on vascular pathology. Due to the influence of diabetes on systemic physiology, it is thought that many changes in retinal vascular cells likely stem from direct biochemical disruptions such as hyperglycemia. Other contributing factors may include circulating cytokines, advanced glycation end products, cholesterol, albumin, and electrolytes, and more complex functional changes such as reduced elasticity in erythrocytes and other blood cells. These and other changes could be responsible for generating the vascular pathologies that have been well established in diabetic retinopathy. There is increasing evidence, however, for involvement of the neural elements of the retina, the neurons and glial cells, and it is no longer clear if the pathological changes in these cells result from vascular dysfunction, such as the reduction in effectiveness of the blood-retinal barrier, or if diabetic physiology induces neural pathology, which in turn gives rise to vascular changes. A third possibility is that early vascular and neural responses to diabetes are independent phenomena that are triggered by different factors.

Oxygen cannot passively diffuse for more than a radius of 100 µm around capillaries. As a result, adequate O_2 supply to each cell depends on effective regulation of the integrity and function of the vascular network. On the other hand, high O_2 tissue levels would result in reactive oxygen species (ROS) generation and cellular damage. Therefore, an optimal O_2 concentration is needed to avoid hypoxia or ROS-mediated cellular injury. The retinal tissue is very active metabolically and, therefore, exquisitely dependent on adequate O_2 supply for its function [ 4 ]. The delivery of oxygen to the retina is dependent not only on systemic blood pressure, hemoglobin content and integrity of local vasculature, but on the level of intraocular pressure and local autoregulatory mechanisms as well. Hypoxia and its sequelae are implicated in the pathogenesis of most retinal diseases, especially those that involve pathologic neovascularization. This is due to the potent stimulation of production of vascular endothelial growth factor (VEGF), mediated by the hypoxia-inducible factor (HIF)-1 pathway, in response to hypoxia.

Proper retinal function requires the presence of a well-defined blood-retinal barrier (BRB). In many of the leading causes of medical blindness this BRB is compromised. Indeed, retinopathy of prematurity and age related macular degeneration both include production of aberrant vessels with poor barrier properties. Further, diabetic retinopathy, the leading cause of blindness in working age adults, involves progressive vision loss and is closely associated with macular edema [ 117 ]. Increased fluid accumulation, as well as lipid and albumin deposits, is believed to be the result of the breakdown of the BRB that normally controls the neuronal environment. Barrier dysfunction results in increased permeability which diagnostically indicates progressive retinopathy [ 32 ]. This chapter will review the normal physiology of the BRB, the changes that occur through the course of diabetic retinopathy, and the known underlying molecular mechanisms that may lead to barrier dysfunction. Elucidating the mechanisms of barrier dysfunction in diabetic retinopathy will further our understanding of its pathogenesis and provide future therapeutic targets.

The human eye is supplied by two vascular systems: the retinal and the uveal vessels. The uveal vascular system consists of the iris, the ciliary body and the choroid. The outer layers of the retina including the photoreceptors are nourished by the choroid, whereas the inner layers of the retina including the retinal ganglion cells are supplied by the retina. Approximately 65% of the oxygen consumed by the retina is delivered from the choroid.

Development of novel molecular biology techniques in the 1970s and 1980s furnished scientists with new tools to advance the study and treatment of human disease. Progress in the understanding of bacterial and viral biology led to innovations in molecular cloning and chimeric plasmid construction. Advances in nucleic acid sequencing allowed researchers to gain a better understanding of genes and the ability to study gene mutations. Unraveling the minutiae of molecular events involved in gene transcription and translation furthered the analysis of cellular pathways and their complex interrelationships. Production of proteins ex vivo allowed physicians to treat diseases such as diabetes with synthetic human insulin, ending the dependency on animal sources.