The exposed surface of the eye is continuously covered by a thin film of fluid, the tear film, which covers the entire ocular surface, including the cornea (the clear “window” of the eye) and conjunctiva (the white part of the eye, which extends under the eyelid). The tear film is a complex fluid that is secreted by several different glands surrounding the eye. The epithelial cells of the ocular surface itself also secrete components of the tear film. The action of blinking spreads the film of tears over the whole surface of the eye and mixes the tears underneath the lids. The tear film serves as an interface between the external environment and the ocular surface and is the first layer of protection for the cornea and conjunctiva. It is constantly responding to stresses that include desiccation, bright light, cold, mechanical stimulation, physical injury, noxious chemicals, and bacterial, viral, and parasitic infection. The tear film also maintains the health of the cornea and conjunctiva by providing optimal electrolyte composition, pH, nutrient levels, and a complex mix of proteins, lipids, and mucin. To respond to these various external and internal requirements, exquisite control of the volume, composition, and structure of the tear film is required. This control arises from regulating secretion from the individual orbital glands and ocular surface epithelia. Regulation of tear secretion provides an extremely stable fluid that protects and maintains the cornea and conjunctiva and ensures that the transparent cornea provides the retina with its window to the world and ensures clear vision.
The ciliary body is a complex, highly specialized tissue that comprises several cell types. The ciliary muscle is situated at the base of the ciliary body and ligaments originating in the ciliary body attach to the lens. Contraction or relaxation of the muscle alters tension on the lens causing it to alter shape and thus shift focus. The surface of ciliary body is elaborated into a series of ridges named ciliary processes. Each ciliary process contains a complicated network of blood vessels that appear leaky to plasma constituents. The ciliary processes are covered by a specialized epithelium bilayer that comprises two distinct epithelial cell types, pigmented ciliary epithelium (PE) and nonpigmented ciliary epithelium (NPE). The ciliary epithelium bilayer constitutes a diffusion barrier between the blood and the aqueous humor in the interior of the eye. Barrier function depends on tight junctions between adjacent NPE cells. The ciliary body is responsible for the production of aqueous humor, a task that requires the polarized cellular distribution and coordinated function of Na, K-ATPase, Na/K/2Cl cotransporter, Na-H exchanger chloride channels and aquaporins in the NPE and PE. There is evidence suggesting an important role for gap junctions between the NPE and PE layers. The rate of aqueous humor secretion can be modified by ion transport inhibitors, by agents that modify gap junction permeability and by maneuvers that change blood flow in the ciliary processes.
The “immune privileged” status of the eye is believed to be based on five different mechanisms including: (1) the blood-ocular barrier, (2) the absence of lympha tic drainage from the eye, (3) soluble factors with immune regulatory properties in ocular fluids, (4) the expression of immune regulatory molecules on the epithelial cells lining the interior of the eye, and (5) tolerance inducing antigen presenting cells (APC). This chapter describes some of these mechanisms. Avoiding intraocular infection and inflammation are of paramount importance to preserve the vision. Different strategies are employed to achieve this goal. Intraocular elimination of pathogens requires a fine balance of the immune system in strictly controlled manner to avoid permanent damage to the delicate structures of the eye. Experimental work during the last decades has disclosed a surprising complexity of regulation. These investigations have primarily focused on the anterior segment of the eye so far, but recent experiments have elucidated some of the strategies that have been used for the posterior segment of the eye.
The sclera is the skeleton of the eye. It defines the size of the eye, provides a stable support for its optical elements, and is essential to the achievement of a focused retinal image. The sclera provides attachment for the extraocular muscles and allows passage of vital structures such as the optic nerve, the arterial blood supply, and the venous drainage system. The overall elastic properties of the sclera neutralize short‐term fluctuations of the intraocular pressure. More specialized functions of the sclera are the drainage of aqueous humor and the mechanical support provided for the fibers of the optic nerve during their passage through the eye wall. Drainage of aqueous humor from the anterior chamber is controlled partly by a specialized part of the sclera, the trabecular meshwork, and partly by the uveoscleral route of which the final segment involves passive transscleral fluid transport. The lamina cribrosa is the specialized part of the sclera that provides mechanical support for the optic nerve as it leaves the eye. Disturbances in the biochemistry and biomechanical properties of the sclera can have severe consequences for the visual function by producing an eye that is not spherical, too long, too short, too rigid, or too elastic. Such disturbances can also interfere with the vascular supply of the eye, the control mechanisms of the intraocular pressure, or the resistance of the transscleral volume flow.
The cornea is the anterior, transparent part of the collagenous wall of the eyeball. It is the window of the eye to the outer world. Its properties allow for the formation of an optical image on the light‐sensitive retina in the back of the eye. This requires transparency and regularity, but it also demands that the gross dimensions of the eye be kept constant. A regulated hydrostatic pressure within a relatively stiff eyeball accomplishes this. The aim of this chapter is to describe the human cornea. Regarding dimensions, there are of course large species variations. Functional aspects have often been studied in animal corneas and usually extended to all other species. Unless otherwise stated the text applies to the “standard human cornea”.
The retinal pigment epithelium (RPE) is a monolayer of cuboidal epithelial cells intercalated between the photoreceptors and the choriocapillaries. The human RPE incorporates some 3.5 million epithelial cells arranged in a regular hexagonal pattern. The density of RPE cells is relatively uniform throughout the retina, approximately 4000 cells/mm2. With age, the cell density decreases particularly in the periphery, where it is reduced to approximately 2000 cells/mm2 in individuals over 40 years. The peripheral RPE cells are larger and more pleomorphic than central cells (Harman et al., 1997; del Priore et al., 2002). In the primate retina, each RPE cell faces 30–40 photoreceptors, a number that is rather constant throughout the retina, although perhaps somewhat lower in the fovea (Robinson and Hendrickson, 1995). In fully developed primate retinas, no mitoses are seen in the RPE, and the epithelium is currently believed to consist of a stable, nondividing, pool of cells (Tso and Friedman, 1967). The retinal membrane of the RPE faces the subretinal space, which is the extracellular space surrounding the photoreceptor outer segments (Figure 1). Between the optic disc and the ora serrata, there are no anatomical contacts between the photoreceptors and the RPE. The RPE forms numerous long microvilli that interdigitate with the rod outer segments. In mammals, the cone outer segments are ensheathed by multilamellar specializations of the RPE, the so‐called cone sheaths. The epithelial cells are bound together by junctional complexes with tight junctions that separate the cells into an apical half that faces the retina and a basal half that faces the choroid. The nucleus and mitochondriae are located in the basal half of the cell. Numerous pigment granules, located predominantly in the apical cytoplasm, give the epithelium its macroscopic black appearance, from which it derives its name. The choroidal side of the RPE directly apposes Bruch's membrane, a pentalaminar, approximately 2 μm thick, elastic membrane. The innermost part of Bruch's membrane is the basement membrane of the RPE. The outer part of Bruch's membrane is the basement membrane of the choriocapillaries. In between are two collagenous layers and a central elastic layer.
Why the eye is round Tears and their secretion Corneal epithelium and corneal stroma Corneal endothelium Ciliary body and ciliary epithelium The lens The vitreous The retina Retinal pigment epithelium The choroid and optic nerve head Innate and adaptive immunity of the eye. Immunology of the eye with focus on control of intraocular inflammatory responses Drug delivery to the eye The sclera
An impressive characteristic about eyes is their round, spherical structure. This chapter explores the optical, mechanical, structural, phylogenic, and ontogenic reasons why eyes are round. This exploration is used as a starting point to describe how the different features of the eye are related to each other, and how the roundness is maintained by the inflow and outflow of fluid in the eye.
The ability of smooth muscles to compensate for increased functional demand is associated with alterations in the expression and function of a number of contractile proteins and other proteins that are involved in excitation-contraction coupling and active force generation. However, continuation of the structural alterations in the muscle cells of the bladder wall leads ultimately to decreased compliance and impaired emptying. Decompensation of the bladder muscle with persistent outlet obstruction is likely to be caused by breakdown of the structure and function of proteins that form the contractile apparatus and those that enable smooth muscle cells to take up, store, and release Ca 2+ . This would affect the activation of the contractile apparatus. In this chapter, we review the contractile proteins that are important for force production and maintenance in smooth muscles and the effect of outlet obstruction on the expression of these proteins.
Weight gain causes high blood pressure in many essential hypertensive patients, and may be a major cause of ESRD. Although the precise mechanisms by which obesity raises blood pressure have not been fully elucidated, weight gain is associated with increased renal tubular reabsorption of sodium and a shift of pressure natriuresis toward higher blood pressures. The increased renal tubular reabsorption is compensated for, in part, by renal vasodilation and glomerular hyperfiltration. However, chronic renal vasodilation also raises hydrostatic pressure and wall stress in the glomeruli which, along with activation of neurohumoral factors and increased lipids and glucose intolerance, may cause glomerulosclerosis and loss of nephron function in obese subjects. The mechanisms by which obesity increases tubular reabsorption and shifts pressure natriuresis toward higher blood pressures are not completely understood, but do not appear to be directly related to hyperinsulinemia. Activation of the sympathetic and renin-angiotensin systems, as well as changes in intrarenal physical forces caused by medullary compression, appear to play a key role in the pathogenesis of obesity hypertension. However, the mechanisms that initiate these changes remain a fruitful area for further investigation, especially in view of the importance of weight gain as a cause of human essential hypertension and ESRD.
The stimulus-response pathways to be discussed in this chapter are the processes by which pharmacological stimuli or membrane depolarization (pharmaco- and electromechanical coupling as defined in 1969 by Somlyo and Somlyo) produce an increase in cytosolic calcium, initiate crossbridge cycling, and result in the development of force. One of the most fascinating, albeit complicating, aspects of smooth muscle is the diversity in the types of cells that mediate or modulate smooth muscle responses. Moreover, each specific category of smooth muscle, such as vascular, airway, or gastrointestinal, responds to any given mediator in a manner appropriate for the physiological function of the organ the smooth muscle lines. For example, longitudinal smooth muscle of the rat stomach responds to endothelin-1 stimulation with the typical contraction; circular smooth muscle of the rat stomach relaxes in response to endothelin-1. One can envision this contrasting response as the perfect mechanism for two muscles to work together rather than in opposition to allow for efficient mixing of gastric contents. This single example is amplified throughout the literature, clearly demonstrating that the stimulus-response pathways in smooth muscle are precisely targeted at the physiological function of the cell.
The microvasculature of the kidney is organized in a manner that permits regional distribution of blood flow to the cortex, outer medulla, and inner medulla. The resistance elements of the cortical microcirculation include interlobular arteries, afferent arterioles, and efferent arterioles. Efferent arterioles that arise from superficial glomeruli supply blood to the cortical peritubular capillary plexus. In contrast, juxtamedullary glomeruli give rise to efferent arterioles that form the vasa recta that supply the medulla of the kidney with blood flow. Descending vasa recta are contractile vessels whose parallel arrangement within outer medullary vascular bundles suggests that they play a role in the neural and hormonal control of blood flow to the outer versus inner medulla of the kidney. Many methods have been devised in an effort to measure regional perfusion of the kidney. Early efforts relied principally on tracer accumulation or tracer transit time. More recent approaches measure either single vessel blood flow with videomicroscopy or local tissue perfusion by laser Doppler. Although no method is ideal, these various approaches have combined, through the efforts of many investigators over many years, to delineate the physiological processes that regulate regional perfusion within the kidney.
The possibility that the renal resistance vessels are implicated in the pathogenesis of hypertension has been confirmed in rat studies demonstrating that the renal afferent arteriole is structurally narrowed in young and adult SHR. Furthermore, it has been demonstrated, in the second generation of crossbred spontaneously hypertensive rats/normotensive rats (SHR/WKY F2 hybrids), that a narrowed afferent arteriole lumen diameter at 7 weeks is a predictor of later development of high blood pressure, indicating that structural narrowing of the renal afferent arteriole could be an important link in the pathogenesis of primary hypertension. The reduced lumen diameter of resistance vessels in hypertension which is generally found, both in humans and in animals, was originally thought to be the result of a growth process in which the media encroached into the lumen. More recently, however, it has been recognized that the narrowed lumen need not be associated with growth, but can be due to a rearrangement of the wall material around the smaller lumen. Indeed, this appears to be the case in renal afferent arterioles, where the decreased lumen is accompanied by a decrease in media cross-sectional area in SHR and could therefore rather be due to inhibited growth. There is evidence indicating that the antihypertensive effect of ACE inhibitors is mediated through renal vascular mechanisms, whereas for calcium antagonists the mechanism is more doubtful. This has been supported by the finding that the ACE inhibitor cilazapril also has a stronger effect on renal afferent arteriole structure compared to the calcium antagonist mibefradil. Moreover, in SHR, ACE inhibitors also have the most persistent effect on blood pressure after treatment withdrawal compared to other antihypertensive drugs. As an overall conclusion, the available evidence points to a key role for the structure of renal afferent arterioles in the pathogenesis of hypertension in the SHR, and the hypotensive action of ACE-inhibitor treatment. Techniques for assessing renal afferent arteriolar structure in humans are at present lacking, but urgently required if the significance of these data for essential hypertension are to be assessed.
