Ординатура / Офтальмология / Английские материалы / Ocular Periphery and Disorders_Dartt, Bex, Amore_2011

of great importance regarding the barrier function of the corneal epithelium. As such, superficial cells form a highly effective, semipermeable membrane on the corneal surface. Not only does the tight junctional barrier prevent decreases in net fluid transport out from the stroma, but it also prevents corneal penetration by pathogens. In addition, gap junctions connect the cells of all layers of the corneal epithelium and function as communication conduits between cells. These tight anatomical arrangements with virtual absence of intercellular spaces contribute to the remarkable transparency of the epithelium, but have deleterious effects when breached after infection (or wounding) and must be restored forthwith in order to restore/preserve visual function.

Upon infection of the corneal epithelium, breakdown of tight junctional integrity occurs due to the loss or disruption of the outermost layers of the epithelium by invading pathogens. This results in a collapse of cell membrane permeability and selectivity, in addition to creating an unrestricted portal for further pathogen intrusion into the cornea until the corneal epithelium and its adhesion molecules are regenerated. Additional adhesion molecules such as selectins, intercellular adhesion mole- cule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are modified after infection due to the secretion of epithelial-derived cytokines, such as TNF-a. As a result, these barriers are further breached to allow the transmigration of inflammatory cells into the injured or infected tissue site. Recruitment of activated leukocytes to sites of infection is essential to the function of both inflammation and innate immunity. However, the extent of leukocyte recruitment contributes largely to the intensity of the inflammatory response, and if this is not well balanced it can result in considerable tissue damage. However, the corneal epithelium does play an active role in regenerating and repairing itself after infection.

CD44 is among the molecules that corneal epithelial cells express to mediate wound healing after infection. This molecule is thought to be involved in cell–cell interactions that provide adhesive strength for the epithelial sheet and in cell–matrix interactions that occur during cell migration and the re-epithelialization process. Basal cells of the corneal epithelium have been demonstrated to secrete APLP2, an amyloid precursor-like protein that is suggested to influence reorganization of the extracellular matrix and dynamic cell–matrix adhesion during re-epithelialization. It has been demonstrated that the corneal epithelium (as well as stromal and endothelial cells) produces and secretes epithelial growth factor (EGF), which is thought to promote cell migration and mitosis of epithelial cells. Corneal epithelial cells then resume expression of molecules such as connexins 45/43 and a6b4 integrin, which participate in the formation of gap junctions and hemidesmosomes/desmosomes, respectively, thus restoring homeostasis of an intact corneal epithelium.

Neuropeptides

Innervation of the Corneal Epithelium

The cornea is among the most densely innervated tissues in the body. In regards to the corneal epithelium, the subbasal epithelial nerve plexus originates from the ophthalmic division of the trigeminal nerve via the anterior ciliary nerves and provides innervation to the basal epithelial cell layer and terminates within the superficial epithelial layers. These nerve fibers are predominately sensory (most classified as nociceptors) and serve a protective role, typically responding to mechanical, thermal, and chemical stimuli. They are stimulated during corneal abrasions and ulcers, and are extremely painful. It is estimated that single corneal sensory neurons support approximately 200 and 3000 individual nerve endings in the mouse and rabbit, respectively, demonstrating the high density of innervation in the corneal epithelium. Corneal nerves in the epithelium have a trophic function, as well. In addition, neuropeptides have been associated with corneal nerves and include: substance P (SP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide (PACAP), and neuropeptide Y (NPY) among others. Nerve damage can lead to transient or chronic neurotrophic deficits following infection of the corneal epithelium. Corneal denervation also significantly impairs the ability of the corneal epithelium to heal itself and predisposes newly healed corneas to periodic, spontaneous epithelial erosions. Although the nerves coursing through the human corneal epithelium are known to produce a variety of neuropeptides, the following sections focus on the importance of two of these molecules: SP and VIP.

Substance P

SP is an 11-amino acid neuropeptide that is largely associated with proinflammatory events during corneal infection, including upregulation of TLR4 and TLR9 mRNA and of cytokines/chemokines IL-1b, TNF-a, IFN-g, and MIP-2 as demonstrated in a murine model of P. aerugi- nosa-induced keratitis. Physiologically relevant concentrations of SP are present in the normal human (and mouse) cornea and corneal epithelial cells express the NK1 receptor, which is the major physiological receptor for SP. The neuropeptide also has been associated with wound healing properties and together with insulin-like growth factor-1 (IGF-1) has been demonstrated to have a stimulatory effect on corneal epithelial cell migration, adhesion, and wound closure.

Vasoactive intestinal peptide

VIP is a 28-amino acid neuropeptide that exerts immunomodulatory properties in the cornea following infection.

It has been demonstrated in a murine model of P. aeruginosa- induced ocular infection that VIP downregulates the production of several proinflammatory cytokines, including: TNF-a, IL-1, IL-6, IL-12, and IFN-g, while stimulating the production of anti-inflammatory cytokines IL-1 receptor antagonist, IL-10, and TGF-b. Macrophage and PMN activation was also shown to be influenced by the presence of VIP. Studies in the mouse further support a role for VIP in wound healing and restoration of immune homeostasis in the cornea; however, it has yet to be determined the extent of which is carried out by the epithelium versus stroma.

Thymosin-b4

As previously stated, after eradication of the invading pathogen, the corneal epithelium must heal and promptly resume normal activity. Thymosin (T)b-4 is a 43-amino acid protein produced by corneal epithelial cells that contributes to the resurfacing of the epithelium and regeneration of cell adhesion molecules to reconstitute the epithelial barrier. Studies have shown that Tb-4 levels are increased in murine corneas during re-epithelialization and also significantly enhance the migration of human corneal epithelial cells through upregulation of molecules associated with cell migration, including laminin-5 and matrix metalloproteinase 1 (MMP-1). Furthermore, Tb-4 modulates corneal cytokine production in an anti-inflammatory manner by downregulating levels of MIP-2 and TNF-a, as demonstrated in the murine cornea. Tb-4 has been demonstrated to inhibit apoptosis of human corneal epithelial cells through inhibition of caspases and suppression of Bcl-2

(an antiapoptotic factor) release from mitochondria. Lastly, this molecule has been demonstrated to modulate matrix metalloproteinase expression and prevent PMN infiltration in an alkali injured mouse cornea model, further supporting a key role for Tb-4 in the repair and remodeling of the injured cornea.

Conclusion

The cornea generates approximately 80% of the eye’s refractive power; therefore, it is imperative that the corneal epithelium possess the ability to effectively and appropriately activate an innate immune response when pathogens are encountered on the ocular surface. The protective mechanisms employed by the epithelium have evolved to balance recognition and elimination of pathogens while limiting corneal damage and preserving the visual axis. In order to do so, the corneal epithelium is able to recognize invading organisms through TLR signaling, generate a network of cytokines and chemokines to recruit and activate host inflammatory cells, produce antimicrobial molecules, and provide activation signals to the complement system, all of which coalesce into an effective and efficient immune response as depicted schematically in Figure 1. The corneal epithelium also possesses the ability to regenerate itself and promote wound healing through expression and secretion of adhesion molecules and Tb-4; this process is enhanced by the presence of corneal nerve fibers that release neuropeptides such as SP and VIP, molecules that further contribute to the healing process and restoration of tissue homeostasis.

See also: Immunopathogenesis of Pseudomonas Keratitis.

Further Reading

Akpek, E. K. and Gottsch, J. D. (2003). Immune defense at the ocular surface. Eye 17: 949–956.

Bora, N. S., Jha, P., and Bora, P. S. (2008). The role of complement in ocular pathology. Seminars in Immunopathology 30: 85–90.

Dohlman, C. H. (1971). The function of the corneal epithelium in health and disease. Investigative Ophthalmology 10(6): 383–407.

Edelhauser, H. F. and Ubels, J. L. (2003). Adler’s Physiology of the Eye: The Cornea and the Sclera. St. Louis, MO: Mosby.

Ganz, T. (2003). Defensins: Antimicrobial peptides of innate immunity.

Nature Reviews Immunology 3: 710–720.

Kumar, A., Zhang, J., and Yu, F. X. (2006). Toll-like receptor 2-mediated expression of b-defensins-2 in human corneal epithelial cells.

Microbes and Infection 8: 380–389.

Lu, L., Reinach, P. S., and Kao, W. W. (2001). Corneal epithelial wound healing. Experimental Biology and Medicine 226(7): 653–664.

McDermott, A. M. (2004). Defensins and other antimicrobial peptides at the ocular surface. Ocular Surface 2(4): 229–247.

McDermott, A. M. (2007). Ocular surface expression and in vitro activity of antimicrobial peptides. Current Eye Research 32(7–8): 595–609.

Muller, L. J., Marfurt, C. F., Kruse, F., and Tervo, T. M. (2003). Corneal nerves: Structure, contents and function. Experimental Eye Research 76(5): 521–542.

Sack, R. A., Nunes, I., Beaton, A., and Morris, C. (2001). Host-defense mechanism of the ocular surfaces. Bioscience Reports 21(4): 463–480.

Sosne, G., Qiu, P., and Kurpakus-Wheater, M. (2007). Thymosin b-4 and the eye: I can see clearly now the pain is gone. Annals of the New York Academy of Science 1112: 114–122.

Szliter, E. A., Lighvani, S., Barrett, R. P., and Hazlett, L. D. (2007). Vasoactive intestinal peptide balances proand anti-inflammatory cytokines in the Pseudomonas aeruginosa-infected cornea and protects against corneal perforation. Journal of Immunology 178(2): 1105–1114.

Uematsu, S. and Akira, S. (2008). Handbook of Experimental

Pharmacology: Toll-like Receptors (TLRs) and Innate Immunity: Toll-Like Receptors (TLRs) and Their Ligands. Berlin: Springer.

Wilson, S. E., Liu, J. J., and Mohan, R. R. (1999). Stromal–epithelial interactions in the cornea. Progress in Retinal and Eye Research 18 (3): 293–309.

Zhang, J., Wu, X., and Yu, F. X. (2005). Inflammatory responses of corneal epithelial cells to Pseudomonas aeruginosa infection.

Current Eye Research 30: 527–534.

Relevant Websites

http://www.nei.nih.gov – Facts about the Cornea and Corneal Disease, National Eye Institute.

http://www.revoptom.com – Handbook of Ocular Disease Management: Cornea.

Glossary

Cell-adhesion molecule – Cell-adhesion molecules are cell surface proteins, usually glycoproteins, that mediate cell–cell adhesion. They play important roles in the assembly and maintenance of tissues, wound healing, morphogenic cellular movements, cell migration, and metastasis. Intercellular adhesion molecule-1 (ICAM-1) functions in leukocyte adhesion and inflammation. Its expression is induced in various cell types by interferon-g (IFN-g), and it mediates interactions with neutrophils in inflamed tissue. Vascular cell-adhesion molecule-1 (VCAM-1) is presented on the surface of various cell types, including endothelial cells, tissue macrophages, fibroblasts, and dendritic cells. Its expression is induced by cytokines, and it plays a key role in the recruitment of eosinophils to sites of inflammation. Collagenase (microbial) – Microbial collagenase is a metalloproteinase produced by bacteria that degrades helical regions of native collagen to yield small protein fragments. The preferred cleavage site is immediately upstream of the glycine residue in the sequence – proline–X–glycine–proline – where X is any amino acid. Six forms (or two classes) of microbial collagenase have been isolated from

Clostridium histolyticum; these proteins are immunologically cross-reactive but possess different amino acid sequences and different specificities. Other variants have been isolated from Bacillus cereus, Empedobacter collagenolyticum, Pseudomonas marinoglutinosa, and species of Vibrio and Streptomyces.

Helper T cell – Helper T cells constitute a specific subpopulation of CD4+ T cells that provides help to other cells of the immune system in mounting an immune response either through direct cell–cell interaction or the secretion of cytokines. They are also referred to as effector T cells. Several distinct subtypes of helper Tcells, designated Th1, Th2, Th3, and Th17, have been identified.

Matrix metalloproteinase – Matrix metalloproteinases (MMPs) constitute an important family of enzymes that regulate composition of the extracellular matrix. They are synthesized as inactive precursor proteins that consist of propeptide, catalytic, and hemopexin domains; proteolytic removal of the propeptide domain results in MMP activation. MMPs are zinc-dependent

endopeptidases that cleave one or several constituents of the extracellular matrix as well as nonmatrix proteins, and they play an important role in cleaving fibrillar collagen types I, II, and III into characteristic three-fourths and one-fourth fragments. Some MMPs are associated with the cell membrane, either through a transmembrane domain or through glycosylphosphatidylinositol anchor; such MMPs may act within the pericellular environment to influence cell migration. MMP-1, MMP-8, and MMP13 are also known as collagenase 1, collagenase

2 (neutrophil collagenase), and collagenase 3, respectively.

Th1 cytokine – Th1 cytokines include interleukin (IL)-2, IFN-g, IL-12, and tumor necrosis factor-b. They are secreted by Th1 cells and play an important role in cell-mediated immunity and chronic inflammation. In general, Th1 responses are stimulated by intracellular pathogens, including viruses as well as certain mycobacteria, yeasts, and parasitic protozoans.

Th2 cytokine – Th2 cytokines include IL-4, IL-5, IL-6, IL-10, and IL-13. They are secreted by Th2 cells and play a key role in the initiation of allergic responses. Th2 responses are also elicited by free-living bacteria and other parasites.

Inflammation

Inflammation is a biological response of the living body to injury or other harmful insults including microbial pathogens, allergens, and physical or chemical agents. It serves to protect the body and is the precursor to wound healing. Classical signs and symptoms of inflammation include redness, swelling, heat, pain, and loss of tissue function. Thus, although inflammatory reactions are well regulated to maintain homeostasis of the body and to promote wound repair, they may result in bodily discomfort. In some instances, however, excessive inflammation may result in tissue damage. Classically, inflammation has been considered to begin with a reaction of vascular tissue that renders vessels permeable to blood cells at the site of injury, resulting in the extravasation of such cells. Recent advances in immunology and molecular cell biology have revealed the mechanisms of inflammation at the level of cellular

interactions and molecular networks. Allergens and infection by pathogens are the major pathological triggers for inflammation at the ocular surface.

The Conjunctiva and Cornea

The ocular surface is composed of the cornea, conjunctiva, lacrimal glands, and associated lid structures. Both the conjunctiva and the cornea are derived from the embryonic epidermis, and they are separated from each other by tear fluid. External insults to the ocular surface evoke different types of inflammatory reactions in the conjunctiva and the cornea that are related to the anatomic differences and physiological roles of these two structures as well as to their connection via tear fluid (Figure 1).

The conjunctiva is a semitransparent membrane that covers the surface of the eye from the back surface of the eyelids to the edge of the transparent cornea. It serves as a barrier at the surface of the eyeball and helps to protect against the invasion of biological, chemical, or physical agents without interrupting the free movement of the eyeball. The surface of the conjunctiva is covered by multiple layers of epithelial cells. The conjunctival epithelium is a relatively inefficient barrier, however, with the result that pathogens, allergens, and biologically active substances readily penetrate into the stroma of the conjunctiva. The conjunctival stroma consists of conjunctival fibroblasts, loosely packed collagen fibers, a vascular system, and abundant immune cells. The triggering of an inflammatory reaction by pathogens or allergens results in enlargement of the blood vessels of the conjunctiva and consequent increased blood flow (hyperemia). The associated

increase in the permeability of the conjunctival vascular system leads to leakage of liquid components and to the development of conjunctival edema. It also allows the infiltration of blood cells into the conjunctival stroma and the consequent activation of conjunctival fibroblasts.

Like the conjunctiva, the cornea faces the external environment. However, unlike the conjunctiva, the cornea is transparent, and its surface must be maintained smooth for the proper transmission of light into the eye. The anatomic structure of the cornea is relatively simple compared with that of the conjunctiva. Its surface is also covered by multiple layers of epithelial cells, but the corneal epithelium provides a much tighter barrier than does the conjunctival epithelium. In the absence of any loss or dysfunction of its component cells, the corneal epithelium prevents the entry of pathogens and allergens into the corneal stroma. The cornea does not contain a vascular system. Although a small number of immune cells such as Langerhans cells, stromal dendritic cells, and macrophages are present in the cornea, its major cellular components are epithelial cells, stromal keratocytes (corneal fibroblasts), and endothelial cells. Both the conjunctiva and the cornea are innervated by the ophthalmic branch of the trigeminal nerve, but the cornea is the most sensitive tissue at the ocular surface, and indeed maybe in the entire body, as a result of the high density of sensory nerve endings in the corneal epithelium.

Tear Fluid: A Reservoir of Inflammatory

Cells and Modulators

Tear fluid functions as a lubricant between the tarsal conjunctiva and the surface of the cornea and serves to

maintain the ocular surface wet. It is also important for ensuring the generation of a clear image on the retina. Moreover, it contributes to the biological defense system of the ocular surface, containing immunoglobulin, lactoferrin, lysozyme, and other protective proteins. With regard to inflammation at the ocular surface, tear fluid provides a pathway for the movement of inflammatory cells – such as neutrophils, eosinophils, and lymphocytes – between the conjunctiva and the cornea. It also serves as a reservoir of various inflammatory cytokines, chemokines, and growth factors as well as of nutrients and oxygen. Collagen-metabolizing enzymes such as matrix metalloproteinases (MMPs) are present in the tear fluid of individuals with certain ocular inflammatory conditions.

Allergic Reactions in the Conjunctiva

The conjunctiva is a common site for allergic reactions (Figure 2). Clinical characteristics of conjunctival allergic disease include hyperemia, edema, the formation of papillary discharge, the development of corneal epithelial disorders, and, in some patients, corneal ulcer. Hyperemia and edema result from dilation and an increase in the

permeability of the vascular system in the conjunctiva. Conjunctival fibroblasts are responsible for the formation of papillae. Mechanical injury caused by papillae as well as the effects of inflammatory cytokines, such as interleukin (IL)-4, IL-13, and tumor necrosis factor-alpha (TNF-a), are responsible for discharge and damage to the corneal epithelium. Disruption of corneal epithelial barrier-function results in the spread of inflammation to the cornea and the development of various types of corneal epithelial disorders. Corneal fibroblasts contribute to the pathology of corneal ulceration. The primary cells that mediate allergic reactions at the ocular surface include mast cells, vascular endothelial cells, eosinophils, T helper 2 (Th2) cells, and conjunctival fibroblasts, with corneal epithelial cells and corneal fibroblasts also contributing in some cases.

Certain allergens that enter tear fluid from the environment are solubilized by the fluid and penetrate through the loose barrier provided by the conjunctival epithelium into the conjunctival stroma. In the stroma, the allergens trigger the secretion of histamine and inflammatory cytokines, such as IL-4, IL-13, TNF-a from mast cells, and IL-3 and IL-5 from Th2 cells. Histamine acts on the vascular endothelium to increase vessel

permeability and induce vessel enlargement, resulting in conjunctival hyperemia and edema. IL-4, IL-13, and TNF-a – released by mast cells – activate conjunctival fibroblasts and trigger their secretion of the chemokines eotaxin and thymus and activation-regulated chemokine (TARC). Eotaxin attracts eosinophils to the interstitial space, and the extravasated eosinophils are then activated by IL-3 and IL-5 released by Th2 cells. TARC attracts Th2 cells into the interstitial space, and these cells then serve as an additional source of IL-4, IL-13, and TNF-a. Exposure of conjunctival fibroblasts to IL-4, IL-13, and TNF-a also stimulates the synthesis of collagen and cell proliferation – effects that give rise to the formation of papillae. The protrusive shape of the papillae results in mechanical injury of both conjunctival and corneal epithelia; such injury together with the effects of IL-4, IL-13, and TNF-a that enter tear fluid from the conjunctiva lead to disruption of the barrier function of the corneal epithelium and to discharge. Eosinophils that enter tear fluid from the conjunctiva are then able to penetrate into the corneal stroma. IL-4, IL-13, and TNF-a also enter the corneal stroma from tear fluid and activate corneal fibroblasts to express TARC, eotaxin, and vascular cell-adhesion molecule-1 (VCAM-1) – a cell-adhesion molecule for eosinophils. The activated corneal fibroblasts also produce MMPs, which degrade collagen of the extracellular matrix in the corneal stroma, resulting in corneal ulceration. TARC released from corneal fibroblasts passes through tear fluid into the conjunctival stroma, where it further promotes the secretion of IL-4, IL-13, and TNF-a by Th2 cells in a vicious cycle. This scenario thus reveals that, although immune cells such as mast cells, Th2 cells, and eosinophils play a prominent role in allergic disorders at the ocular surface, resident fibroblasts in both the conjunctiva and cornea also contribute to the inflammatory process.

Infection of the Conjunctiva or Cornea

The clinical characteristics of infection at the ocular surface include swelling, hyperemia at the conjunctiva, discharge, and epithelial defects and ulceration in the cornea. As with allergic reactions, the reactions of the conjunctiva and cornea to infection differ (Figure 3). The vascular system of the conjunctiva ensures a robust immune response to infection in this tissue, with conjunctivitis being a relatively mild clinical condition. However, the cornea is avascular and possesses few immune cells, with the result that corneal infection is more serious and may become sight threatening.

If a pathogen survives the biological defense system in tear fluid, it readily penetrates the conjunctival epithelium and triggers the dilation and permeabilization of conjunctival blood vessels, resulting in swelling and

hyperemia. Neutrophils and Th1 cells enter the conjunctival stroma from the bloodstream and serve as the second line of defense against pathogens. Both neutrophils and Th1 cells secrete IL-1, with Th1 cells also secreting interferon-g (IFN-g). These cells and cytokines may be sufficient to inactivate the pathogen and limit the inflammatory response to the conjunctiva. However, pathogens also act on conjunctival epithelial cells to trigger the secretion of IL-8, IL-6, and TNF-a. These cytokines together with IL-1 and IFN-g can enter tear fluid and, in the presence of damage to the corneal epithelium, may penetrate into the corneal stroma and activate corneal fibroblasts.

The tight barrier provided by the corneal epithelium normally prevents the entry of pathogens into the cornea. However, corneal epithelial injury can result in pathogen penetration into the corneal stroma. Pathogen-associated various factors such as lipopolysaccharide (LPS) of Gram-negative bacteria and peptidoglycan (PGN) of Gram-positive bacteria are recognized by toll-like receptors (TLRs) on the surface of corneal fibroblasts and trigger the production of IL-8 and the expression of intercellular adhesion molecule-1 (ICAM-1) by these cells. IL-8, IL-6, TNF-a, IFN-g, and IL-1 that enter the corneal stroma via tear fluid also induce IL-8 production by corneal fibroblasts. IL-8 then attracts neutrophils exuded (extravasated) from conjunctival blood vessels into the corneal stroma, and these cells interact with corneal fibroblasts via ICAM-1. IL-1 released from neutrophils further stimulates corneal fibroblasts.

Corneal infection is associated with the production of two types of collagen-degrading enzymes: collagenase released from the pathogen and MMPs released from corneal fibroblasts. These enzymes destroy stromal collagen, eventually resulting in the development of corneal ulcer. Collagen destruction by MMPs released from activated corneal fibroblasts may continue even if the pathogen has been killed by antimicrobial treatment. Neutrophils were originally thought to destroy stromal collagen, but these cells were subsequently found to promote the production of MMPs by corneal fibroblasts rather than to degrade the collagen themselves. As with ocular allergy, corneal fibroblasts thus play a key role in the progression of the inflammatory response to corneal infection.

Tear Fluid as a Diagnostic Indicator of

Inflammation

The measurement of inflammatory cytokines or chemokines and the cellular components of tear fluid provides clinically important information on inflammation at the ocular surface. The presence of eosinophils in tear fluid thus confirms a diagnosis of allergic inflammation,

whereas the presence of neutrophils is indicative of infectious inflammation.

In addition to being of diagnostic value, the condition of the tear fluid can affect the progression of ocular surface inflammation. In individuals with dry eye, for example, the decrease in tear secretion and small volume of tear fluid may result in concentration of inflammatory cells and proteins. The condition of tear fluid should thus be taken into account in the treatment of patients with ocular surface inflammation.

Connection of the Conjunctiva and Cornea via Tear Fluid

The surfaces of both the conjunctiva and the cornea are covered by epithelial cells. However, the biological responses of these two tissues to allergens or to pathogens differ markedly. The conjunctiva has a prominent vascular system and contains abundant immune cells, whereas the cornea is transparent and avascular and contains few immune cells. These anatomic differences between the

conjunctiva and cornea are reflected in the types of inflammatory condition that affect them. The conjunctiva is the principal target tissue for allergic reactions at the ocular surface, whereas the cornea is the main target for microbial infection or injury. The vascular system of the conjunctiva serves as a key source of immune cells in each of these conditions. The cornea is also affected by inflammatory reactions that occur in the conjunctiva, with the tear fluid that covers the surface of both the conjunctiva and the cornea serving as a conduit for the exchange of immune cells, cytokines, chemokines, and growth factors.

The concept of inflammation was first described more than 2000 years ago as redness and swelling with heat and pain by Celsus. In the nineteenth century, the concept of loss of tissue function associated with inflammation was recognized. Recent advances in cell and molecular biology have revealed the cytokine and chemokine network that underlies inflammation. However, the availability of effective anti-inflammatory drugs other than steroids remains limited. Nonsteroidal antiallergic drugs have been developed and are effective for the treatment of allergic conjunctivitis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also effective in ameliorating inflammatory reactions.

However, anti-inflammatory agents that halt tissue destruction are needed. Further characterization of the bidirectional regulation of conjunctival and corneal resident cells via cytokines and chemokines, as well as immune cells, released into tear fluid may provide a basis for the development of new drugs effective for the treatment of inflammation at the ocular surface.

See also: Adaptive Immune System and the Eye: Mucosal Immunity; Adaptive Immune System and the Eye: T Cell-Mediated Immunity; Antigen-Presenting Cells in the Eye and Ocular Surface; Conjunctiva Immune Surveillance; Conjunctival Goblet Cells; Defense Mechanisms of Tears and Ocular Surface; Dry Eye: An Immune-Based Inflammation; Immunopathogenesis of Pseudomonas Keratitis; Molecular and Cellular Mechanisms in Allergic Conjunctivitis; Ocular Mucins; Overview of Electrolyte and Fluid Transport Across the Conjunctiva.

Further Reading

Hazlett, L. D. (2005). Role of innate and adaptive immunity in the pathogenesis of keratitis. Ocular Immunology and Inflammation

13: 133–138.

Kolaczkowska, E., Chadzinska, M., and Plytyez, B. (2008). Basic concepts of inflammation – from pioneer studies until now. In: Romano, G. T. (ed.) Inflammation Research Perspectives, pp. 113–168. New York: Nova Science Publishers.

Kumagai, N., Fukuda, K., Fujitsu, Y., Yamamoto, K., and Nishida, T. (2006). Role of structural cells of the cornea and conjunctiva in the pathogenesis of vernal keratoconjunctivitis. Progress in Retinal and Eye Research 25: 165–187.

Kumar, V., Abbas, A. K., Fausto, N., and Mitchell, R. N. (2007). Robbins Basic Pathology, 8th edn., pp. 31–58. Philadelphia, PA: Saunders-Elsevier.

Ley, K. (2001). History of inflammation research. In: Ley, K. (ed.) Physiology of Inflammation, pp. 1–10. New York: Oxford University Press.

Pearlman, E., Johnson, A., Adhikary, G., et al. (2008). Toll-like receptors at the ocular surface. Ocular Surface 6: 108–116.

Tuli, S. S., Schultz, G. S., and Downer, D. M. (2007). Science and strategy for preventing and managing corneal ulceration. Ocular Surface 5: 23–39.

Glossary

Angioblast – Mesenchymal tissue that differentiates into blood cells and vascular endothelium. Angiogenesis – Formation of new blood vessels by outgrowth from preexisting vessels. Intussusception – Formation of new blood vessels by splitting of existing vasculature.

Keratoplasty – Corneal transplantation. Vasculogenesis – De novo blood-vessel formation from endothelial progenitor cells.

Introduction: Angiogenesis and

Lymphangiogenesis

(Hem)angiogenesis describes the process of new bloodvessel formation by outgrowth from preexisting vessels. Accordingly, lymphangiogenesis means the formation of lymphatic vessels from preexisting ones. Both processes are precisely regulated and play an essential role in physiological and pathophysiological events in the organism.

In the context of the eye, pathological new blood and lymphatic vessels are associated with numerous disorders reducing visual acuity.

New blood-vessel formation in the organism is achieved either by angiogenesis or by vasculogenesis. Both processes can be distinguished from each other and strongly differ in the way the vessels arise. Vasculogenesis occurs mainly during embryogenesis and implies de novo blood-vessel formation by endothelial progenitor cells. During embryonic development, angioblasts, a subset of mesodermal cells, differentiate into endothelial cells and form the early vascular plexus. After establishing the primary vascular plexus, new blood vessels can be generated through angiogenesis that means by sprouting from preexisting blood vessels or by intussusception (nonsprouting angiogenesis). Angiogenesis and vasculogenesis normally occur during embryonic development. For the vascularization of the central nervous system (CNS) and the kidneys, angiogenesis seems to be the more important process. Following birth, most blood vessels remain in a quiescent state except for the once in the hair cycle, in the female reproductive system and during wound healing. In the case of unregulated angiogenesis, however, neovascularization can occur in the adult organism and usually is associated with

diseases such as arthritis, tumors, or corneal and retinal disorders.

During early development of the retina, which is embryologically derived from the diencephalon, vasculogenesis and angiogenesis take place. In 1970, Ashton first described the mechanism of vasculogenesis for blood vessel formation in the retina of the human embryo. He proposed that primitive mesenchymal cells, after invading the retina, differentiate into endothelial cells, thereby, forming a capillary network. Nowadays there is evidence that vasculogenesis and angiogenesis both are responsible for the vascular development of the human fetal retina. Hughes and colleagues suggest a mechanism where vasculogenesis pioneers the establishment of a rudimentary vascular plexus, whereas angiogenesis provides further expansion of the vascular network and cares for increasing vessel density. Considering the fact that the retina is a highly metabolic active tissue both mechanisms complement one another and contribute to meet the metabolic requirements of the developing retina. The developed retina is a highly vascularized tissue that shows a dual blood supply. The inner layer of the retina is supported by the centralis retinae artery, originating from the arteria ophthalmica. The outer layer – especially the receptors – receive blood from the arteriae chorioideae.

In general, the eye is an efficiently vascularized organ and shows a significantly higher blood circulation compared to other organs with the same volume; however, there are exceptions at the anterior pole of the eye being completely devoid of blood and lymph vessels. Whereas posterior structures like the retina, as mentioned earlier, show a strongly branched blood-vessel network, the sclera is relatively low vascularized and the adjacent cornea and the vitreous even are devoid of blood and lymphatic vessels. Keeping up corneal avascularity comprises an active process and needs the balance between angiogenic and anti-angiogenic factors. In this process, the cornea maintains the transparency even under inflammatory or other pro-angiogenic conditions by different molecular mechanisms which are not completely elucidated to date. This ability is called the corneal angiogenic privilege.

Corneal Angiogenic Privilege

Corneal Avascularity

The corneal angiogenic privilege normally prevents the ingrowths of new vessels in the cornea even under