A corneal ulcer is defined as a disruption of the epithelial layer with involvement of corneal stroma. This condition is associated with inflammation, either sterile or infectious.
Pathophysiology
An understanding of the pathophysiology of sterile corneal ulcer requires the review of the processes involved in wound healing epithelium and stroma, and examining the role of precorneal tear film, corneal nerves, proteolytic enzymes, and cytokines.
Epithelial wound healing
corneal ulceration always begins with epithelial defects. Persistent corneal epithelial defect allows for the exposed stroma external environment and allow the degradation of stroma.
Within minutes after small corneal epithelial injury, cells at the edge abrasion began to migrate centripetally to cover the defect with a rapid on the level of 60-80 pM / h. 4-5 hours long delays seen in larger defects. This delay is necessary to change the cell preparation prior to rapid cell movement.
epithelial cells adjacent to the defect area average, lose their hemidesmosome attachment, and migrate as a focal zone of contact that exists between cytoplasmic actin filaments and extracellular matrix proteins. Vinculin, plasma protein, fiber link to Talin, which is a cell membrane protein. This, in turn, is associated with integrin. Contraction of actin fibers pull the cell body forward.Vinculin, integrin, fibronektin, fibrinogen, and fibrin is formed continuously and cleaved to allow cell migration. Plasmin is a protease responsible for splitting of fibrinogen and fibrin in this zone contact focus.
Basement membrane is also important for epithelial migration, and basement membrane abnormalities in the structure, whether due to trauma (eg, recurrent erosion syndrome) or dystrophy (eg, basement membrane dystrophy), can lead to persistence of epithelial defects and ulceration corneal stroma.
After 24-30 hours, mitosis began to restore the epithelial cell population. Basal and limbal stem cells contribute to mitosis. A sufficient supply of progenitor stem cells to facilitate epithelial cell proliferation is important for the cornea. Lack of limbal stem cells, either from disease (eg, aniridia) or trauma (eg, chemical burns), can inhibit epithelial wound healing is adequate.
Stromal wound healing
Stromal wound healing occurs through stromal keratocyte migration, proliferation, and deposition of extracellular matrix molecules, including collagen (type III in particular), adhesion proteins (eg, fibronektin, laminin), and glukosaminoglikan. This process is facilitated by phenotypic changes of keratocytes into myofibroblasts still active, the task is mediated by transforming growth factor-beta (epithelial origin suspected).
Stromal necrosis and degradation
Corneal wound repair process is closely related to a complex inflammatory response that must be precisely regulated to ensure proper healing.
Invasion of monocytes / macrophages are very important in wound healing, however, in the corneal stroma, excessive infiltration of monocytes / macrophages are considered less well because they remove matrix metalloproteinases (MMPs) and other unwanted proteins for tissue healing. A number of cytokines and growth factors that up-regulated in corneal cells further contribute to tissue inflammation.
Matrix metalloproteinases (MMPs) are a group of structurally related endopeptidases that require metal cofactors. To date, more than 25 have been identified and categorized into 6 groups according to their substrate specificity. The main function is to lower the extracellular matrix metalloproteinase components and basement membranes. MMP-2 and MMP-9 are known as gelatinases and are involved in the splitting of collagen type IV, V, VII, and X, and fibronektin, laminin, elastin, and gelatins. MMP-1 (neutrophil collagenase) and MMP-8 (fibroblast or keratocyte collagenase) involved in the splitting of collagen types I, II, and III.
Barely detected in unwounded cornea, MMPs is induced during wound healing. Metalloproteinases are secreted as proenzymes by neutrophil infiltration injury, injured epithelial cells and keratocytes. They are activated by proteolytic cleavage of the N-terminal region in the extracellular compartment. In vivo, tissue inhibitor of metalloproteinases (TIMPs) inhibit the activity of collagenase. TIMPs represent multigene family that includes at least 4 members. They exert their action by blocking the activation of MMPs and inhibits proteinase activity.
Relatively higher level of collagenolysis relative to the synthesis of expected causes of degradation, thinning corneal ulceration, and, therefore, progressive corneal stroma. MMPs are induced at the transcriptional level by various cytokines and growth factors, such as interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), epidermal growth factor (EGF), is derived factor platelet growth (PDGF), fibroblast growth factor (FGF), and growth factors alter-beta (TGF-beta).
synthetic inhibitors of mammalian metalloproteinases (SIMP) has been studied to determine their effect on the cornea after alkali burn. It has been shown that SIMP effectively inhibit corneal ulceration when started earlier in the treatment of well established ulcers.
Studies have shown a role for extracellular matrix metalloproteinase inducer (EMMPRIN), enrichment of cell membrane glycoproteins in epithelial cells during corneal wound healing. It has been shown that it is up-regulated in epithelial cells by EGF and TGF-beta. This, in turn, encourages the fibroblasts, with direct interaction, to improve their own level of EMMPRIN, leading to induction of MMP. Inhibition of EMMPRIN may be a promising therapeutic strategy in situations of future excess extracellular matrix degradation associated with chronic wounds healing.
Because all of metalloproteinase enzymes require metal cofactors Ca2 + and Zn2 +, chelating agents such as ethylenediaminetetraacetic acid (EDTA), acetylcysteine, and penicillamine inhibits collagenase activity, but this agent has been found to have limited efficacy in vivo. Tetracyclines also have anticollagenolytic activity.
As a result of the disruption of collagen, collagen products tripeptide released. It is chemotactic for neutrophils, which migrate into the injured tissue where they release additional MMPs and superoxide radicals. The agents potentiate further action collagenolytic and degradation of the cornea. Superoxide dismutase (SOD) reduces superoxide radical enzymatic hydrogen peroxide, thus effectively eliminating a highly reactive oxygen metabolites before further damage. SOD isozymes are found in the cornea of mammals. Therefore, the use of topical SOD is very helpful in preventing damage to the cornea. Studies have shown beneficial effects of SOD lecithinated, who was arrested on the surface of the eye longer than native SOD when applied as eye drops solution.
In the cells along the leading edge of the wound, there is a specific activation of Ser / Thr kinase, Cdk5. Cdk5 activity limiting the accumulation of active Src. Active Src promotes epithelial cell migration. However, excessive Src activity can also cause degradation of E-cadherin and complete loss of cell-cell adhesion, so that the activity and localization must be tightly controlled.Inhibiting Cdk5 activity in organ culture after debridement wounding significantly increased levels of migration, but also causes some cell separation along the leading edge.
Topical application Cdk5 inhibitor, olomoucine, increase the rate of debridement wound closure without sufficient cause dissociation or detachment of epithelial cells.
The role of corneal nerves
cornea is densely innervated by fibers from the ophthalmic division of trigeminal nerve and sympathetic nerve fibers from the superior cervical ganglion. provide a protective corneal nerve function and trophic importance, and disruption of corneal innervation may result in epithelial changes in morphology and function, poor tear film, and delay wound healing. Decrease in corneal sensation of denervation may result in stromal ulceration and perforation. These results are ulcers of the metabolic rate and decreased mitosis in the corneal epithelium and reduced acetylcholine, choline acetyltransferase, and substance P concentration.
In 1954, a classic experiment Sigelman et al showed that changes in the surface of the eye associated with neurotrophic keratitis in animals survive despite denervation tarsorrhaphy, showing trophic effects of corneal nerves. Evidence suggests that the loss of sensory neurons leads to severe impairment of acetylcholine in an otherwise rich network of acetylcholine , resulting in a relative decrease in the growth of epithelial cells.
Another study due to depletion of substance P associated with sensory denervation as a cause of changes associated with neurotrophic keratitis. It has been reported that substance P administered insulin like growth factor 1 (IGF-1) or EGF synergistically facilitate corneal epithelial migration and adhesion. Nakamura and coworkers (1999) determined that only four amino acid sequence (FGLM) from terminal C substance P is necessary.6 These findings have implications for the clinical use of topical neuropeptides, because full-length peptide is more easily damaged and inactive by peptidases in tear film and corneal epithelium.
Clinical trials of nerve growth factor (NGF) by Bonini et al (2000) showed a beneficial effect in promoting corneal epithelial wound healing and, possibly, in increasing sensitivity in patients with keratitis.7 neurotrophic mechanism of action of NGF on the ocular surface is not well defined. This may involve a direct mechanism of sensory innervation and epithelial cell proliferation and differentiation. Indirect mechanisms, such as increased neuropeptides that promote epithelial healing or summon immune cells through the release of cytokines, can also be involved.
Precorneal tear film role in ulceration
Exposure of the bare corneal stroma to a secondary environment for wound healing deficiencies or disorders thought to contribute to the degradation of epithelial stromal through environmental factors, cytokines, lytic enzymes, and neutrophils in tear film. Direct adhesion of neutrophils to the corneal stroma are theoretically possible hydrolytic and collagenolytic enzymes, including (neutrophil collagenase), MMP-8, to contribute to the degradation of extracellular matrix of corneal stroma.
Dohlman et al (1969) and Kenyon et al (1979) showed that fixed on the lens methylacrylate applied to the rabbit alkali burn model of corneal ulcer to protect the stroma of collagenolysis by neutrophils and epithelial cells. injured, Keratocyte fibroblasts may also contribute to this environment . Prevention of infiltration of neutrophils and promotion of epithelialization is expected at least some of the mechanisms responsible for beneficial effects of the use of amniotic membrane graft in preventing stromal ulceration.
In addition, cytokines, such as hepatocyte growth factor (HGF), keratocyte growth factor (kgf), and EGF, produced by the lacrimal gland and, thus, present in tears. HGF up-regulated in response to corneal injury in parallel with the water increase tear production. In wounded corneas, these cytokines may play an important role in regulating epithelial healing. inflammatory cytokines, including IL-1alpha, which was detected in normal human tears and may be important in causing further degradation of the corneal stroma, either directly by inducing apoptosis of keratocyte or by recruiting inflammatory cells via their chemotactic properties. In addition, irregular tear film and reduced tear film breakup time over the area of bare stroma can cause delle effects that can contribute to the cellular environment unfavorable for the survival and proliferation of stromal keratocytes.
Role of cytokines
The function of complex autocrine and paracrine cytokines involved in the interaction between corneal epithelium and stromal keratocytes is important in achieving the appropriate response to corneal wound healing. While their right triggering and interaction are still being discussed, cytokines can induce and mediate many of the basic steps involved in wound healing.
epithelial cell migration, proliferation, and differentiation is influenced by the cytokines stromal keratocyte, kgf and HGF.cornea is not unique to the stromal-epithelial interactions these 2 cytokines, which is a mediator of such interactions in the skin, breast, and lung. Although this cytokine expression profile lends itself to a linear interpretation of their stromal-epithelial interactions, this cytokine clearly is modulated further in vivo with the effects of other cytokines and receptors is cut from the molecule.
In what is probably just the tip of the iceberg in relation to the understanding of interaction of cytokines, both kgf and HGF mRNA production is altered by cytokines fibroblasts, EGF, TGF-alpha, PDGF, and IL-1. In addition, EGF, PDGF, IL-1alpha, IL-6, and TNF at low concentrations appear to increase fibronektin (FN)-induced epithelial cell migration.
Must not be defeated by the influence of stromal, epithelial cells modulate keratocyte response is important for epithelial cell injury.Keratocyte wound healing process, including the production of MMP and regulations, HGF and production kgf, and keratocyte apoptosis, mediated through various cytokines, including stimulators such as IL-1 and soluble Fas ligand and the main inhibitor of TGF-beta2. Anterior stromal keratocyte cell death is an important feature of the injured corneal stroma and degradation.
Beyond keratocyte cell death caused by mechanical injury or necrosis associated with infiltration of neutrophils, IL-1-and Fas ligand-mediated apoptosis is an important stromal response to epithelial injury. Since both of these cytokines can be produced by keratocytes, autocrine modulation of these responses may occur.IL-1 and PDGF also regulate MMP expression in stromal keratocytes. Keratocyte appropriate response to IL-1 likely will be determined by the cytokine environment in which keratocyte be targeted. Other cytokine systems have shown fibroblast apoptosis include TNF and bone morphogenic protein (BMP).
Studies have shown that autologous serum and umbilical cord serum harbor many growth factors and neuropeptides such as EGF, TGF-beta, vitamin A, fibronektin, substance P, IGF-1, NGF, and other cytokines are important for the differentiation, proliferation, and maturation of epithelial surface of the eye.Treatment with autologous serum and umbilical cord serum eye drops seem promising for the restoration of the integrity of the epithelial surface of the eye in patients with neurotrophic keratitis and severe dry eye syndrome.
Platelets are known for their ability to heal wounds and internal epithelia. They have a storage pool of growth factors, including platelet-derived growth factor, TGF-beta, epithelial growth factor, fibroblast growth factor, insulin like growth factor I, and vascular endothelial growth factor. autologous platelet-rich plasma has a large number of growth factors that have been found to promote active corneal ulcer healing and to reduce pain and inflammation.11
Platelet-activating factor (PAF) is a potential bioactive lipid produced in the cornea after injury. Corneal cells synthesize PAF as early as 30 minutes after injury and increased accumulation was observed at a later time, which, in part, because of the presence of inflammatory cells that arrive in the cornea and actively produce PAF. PAF is a powerful inflammatory mediator and inducer of the expression of specific genes, such as some metalloproteinases, urokinase plasminogen activator, and TIMPs. This delay corneal epithelial wound healing by inhibiting epithelial cell adhesion to basement membrane and stromal cells by enhancing apoptosis. All activities provided by the PAF receptor-mediated. Corneal epithelial cells, keratocytes, and endothelial cells express the PAF receptor, and, on corneal epithelial cells, injury up-regulate PAF receptor gene expression. Role of PAF receptor antagonist in preventing injury to the cornea being investigated.
Plasminogen is synthesized in the cornea and can be activated to plasmin by plasminogen activators. This synthesis is stimulated by IL-1alpha and IL-1beta. In turn, plasmin can activate latent collagenase. This system may cause degradation of collagen from corneal ulceration. Research has shown that the UPA (urokinase plasminogen activator), but not TPA (tissue plasminogen activator), induced in epithelial cell migration during corneal epithelial wound healing. Amiloride, a specific inhibitor of UPA, UPA effectively decreased activity in the cornea and the tear fluid and positively affect the healing of the cornea.
Most of the inflammatory cytokines using nuclear factor (NF)-kB pathway to signal. Saika et al studied 2005 mouse corneal alkali burn model to evaluate the therapeutic potential of topical administration of SN50, cell-permeable peptide inhibitor of NF-κB.12 They showed that administration of topical SN50 prevent damage to the epithelium and corneal ulceration after alkali central burn.
Thymosin beta-4 is a water soluble polypeptides that promote corneal wound healing and decrease inflammation.13 Thymosin beta-4 interfere with NF-kB and suppress the signal path of NF-kB phosphorylation, activity, and nuclear translocation in cell culture of human corneal epithelium. Thymosin beta-4 can potentially be used as a potent anti-inflammatory therapy in inflammatory corneal conditions.
Saika et al (2007) concluded that the overexpression of gamma-peroxisomes proliferator-activated receptor (PPARgamma) may be an effective new strategy for the treatment of eye surface burns.14 Adenoviral gene introduction of PPARgamma inhibits activation of ocular fibroblasts and macrophages in vitro and also caused anti response antifibrogenic-inflammatory and in a mouse corneal alkali burn.
Cytokines and trophic factors from nerve cornea, tear film, conjunctiva, conjunctival vessels, endothelium, and anterior chamber may have an important modulating effect on the response of healing corneal epithelium and stroma and, thus, corneal ulceration.
Frequency
United States
The incidence depends on the etiology of corneal ulcers.
Mortality / Morbidity
scarring of the cornea, decreased vision, neovascularization, perforation, and blindness associated with this condition.
Sex
Because of the increased incidence of injury, this condition can be seen more often in men than women.
Clinical History
The diagnosis of this condition, to distinguish between infectious and non-infectious etiology is very important. Because the clinical management of corneal ulcer depends on its etiology, obtain all important factors (eg, endogenous, exogenous, local) is important.Therapy for persistent sterile ulcerations should be considered only after quite overcome infectious and systemic factors.
Key points to assess in obtaining the history of patients with corneal ulcers were as follows:
Before the eyes of history - Before the ocular and adnexal surgery, or repeated episodes of infection (eg herpes), and corneal dystrophy. Past medical history - Immune status, collagen vascular disease, systemic infection, diabetes, malnutrition, alcoholism, and chronic debilitating diseases. History of trauma - foreign bodies and their origin (eg, soil, vegetation, water), chemical splash, and the blister cap. Contact lenses are used - Type, frequency, duration, use overnight, and cleanliness.
Drugs - in the eye and vice versa
The history of this disease - Duration, ocular symptoms (eg, level of pain vs. clinical impression), and chronicity. Social History - Patients from endemic areas to process certain infections, nutritional status, and any abuse of alcohol. The etiology of the ulcer is often multifactorial sterile, in this setting, identifying the coconspirators in this process is important. A comprehensive evaluation to identify potential factors, including drugs (medicamentosa), corneal sensation disorders (neurotrophic), exposure (eg, lagophthalmos), and reduced tear production (sicca), required in most cases of persistent noninfectious ulcers.
Physical
Physical examination should begin with gestalt impression of the whole patient, taking into account the following:
- General health of patients - Skin lesions, abnormal skeletal, mental status, level of discomfort, hearing aids, scars, and limitations for ambulation that may indicate a systemic disease
- Local adneksa eye and related organs - eyelids, lacrimal system, blink rate, scars, mucous membranes (eg, lips / mouth, conjunctiva), orbit, symmetry, and evidence of inflammation or infection
- Palpation - If indicated for the resilience of the orbital (thyroid / exposure), lymphadenopathy, and lacrimal or other adnexal masses
Assessment of vital signs eye - (. Corneal sensation should be checked before tonometri) Visual function, corneal sensation, tonometri, pupil function, and eye motility
On slit lamp examination of the cornea, note the appearance and evaluate the following:
- Conjunctiva, sclera, and lids - Erythema, patterns of injection (ciliary flush, spread or depth), nodules perilimbal, discharge, lid closure, lid margin disease, and flipped the lid over to exclude foreign body syndrome and floppy eyelid
- Tear Film - Degree, symmetry, regularity, and presence of debris
- Epithelial - epithelial defect location (local or spread), regularity, and microcysts
- Stroma - Thinning and presence / pattern of infiltrates (eg, ring, hairy, radial)
- Endothelium - Keratic precipitates
- Anterior chamber - Hypopyon and inflammation
- Corneal sensation
- Symmetry between the eyes
- Fluorescein examination
- Dilated examination (if necessary)
Cause infection (which need to be ruled out first) as follows:
- Bacteria (focal infiltrate)
- Mushroom (vegetable matter, for example, a branch, the emergence of satellite lesions; feathered border to infiltrate; chronic)
- Acanthamoeba (contact lens wear, tap water, soil, severe pain out of proportion to the display, keratitis radial, ring ulcer)
- Herpes simplex virus (history, dendrites, decreased sensation, disciform keratitis, increased intraocular pressure)
- Herpes zoster virus (vesicles more dermatomes; pseudodendrites, there is no true terminals light; decreased sensation, increased intraocular pressure)
- Contact lens-related (infectious or not infectious)
- Chemical burns, including alkaline / acid burn (check the pH)
- Thermal / radiation burns (history)
- Sicca (filament, Sjögren's syndrome)
- Neurotrophic (decreased sensation, may have minimal pain, edge milled, oval, the lower half of the cornea, may be quite thin, herpes zoster / herpes simplex virus, postsurgery, the fifth-nerve paralysis, chemical burns, abuse of topical anesthesia, neurotrophic keratitis, diabetes mellitus, multiple sclerosis)
- Exposure (lagophthalmos, lid abnormalities, inadequate blinking, facial palsy, proptosis, thyroid disease)
- Medicamentosa (drops)
- Atopic (history, follicle / papilla)
- Vitamin A deficiency (primary deficiency due to a prolonged food shortage; deficiency secondary to diseases that interfere with fat absorption and storage, for example, celiac disease, cystic fibrosis, cholestasis)
- Basement membrane abnormalities (microcysts, evidence of map-dot-fingerprint or anterior stromal dystrophies, history of trauma, dystrophy, etc.)
- Artificial
- Wegener's granulomatosis
- Rheumatoid arthritis
- Other collagen vascular disease (indicated by the history and findings related to systemic)
