Maintenance and repair of corneal stromal extracellular matrix (ECM) requires a tightly coordinated balance of ECM synthesis, degradation and remodeling in which proteolytic enzymes (proteinases) perform important functions. There are natural proteinase inhibitors present in preocular tear film (PTF) and cornea simultaneously with proteinases that prevent excessive degradation of normal healthy tissue. Disorders occur when there is an imbalance between proteinases and proteinase inhibitors in favor of the proteinases, causing pathologic degradation of stromal collagen and proteoglycans in the cornea. Two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, are of major importance in terms of remodeling and degradation of the corneal stromal collagen. Immunohistochemical studies have shown different origins of MMP-2 and -9. MMP-2 is synthesized by corneal keratocytes and performs a surveillance function in the normal cornea, becoming locally activated to degrade collagen molecules that occasionally become damaged. Alternatively, MMP-9 may be produced by epithelial cells and polymorphonuclear neutrophils following corneal wounding. Because the cornea is in close contact with the preocular tear film (PTF), proteinases have been evaluated in the PTF. In damaged corneas, total proteolytic activity in the tear fluid was found to be significantly increased compared to normal eyes and contralateral eyes. Studies analyzing the proteolytic activity in serial PTF samples during corneal healing led to the following conclusions: ulcerative keratitis in animals is associated with initially high levels of tear film proteolytic activity, which decrease as ulcers heal; proteinase levels in melting ulcers remain elevated leading to rapid progression of the ulcers. The success of medical and surgical treatment of the corneal ulcers is reflected by the proteolytic activity in tears. In animals, successful treatment leads to a rapid reduction in tear film proteolytic activity that corresponds with the improvement in the clinical signs of corneal ulceration. The in vitro effects of various compounds on proteolytic activity in the tear fluid of animals with ulcerative keratitis have been evaluated and their important inhibitory effects have been confirmed. Because these various compounds utilize different mechanisms to inhibit various families of proteinases, a combination of these proteinase inhibitors may be beneficial.

Proteinases of the cornea and preocular tear film

Objective—To examine in vitro effects of various antiproteolytic compounds on activity of matrix metalloproteinase (MMP)-2 and -9 in the tear film of horses with active corneal ulcers. Sample Population—Samples of tear film obtained from the eyes of 34 horses with active ulcerative keratitis. Procedure—Horses were sedated, and tear samples were collected from the lower fornix of 34 ulcerated eyes by use of capillary tubes. The protease inhibitors 0.2% EDTA, 0.1% doxycycline, 10% N-acetylcysteine (NAC), 0.1% solution of a modified dipeptide that contains hydroxamic acid (ie, ilomostat), 0.1% α1-proteinase inhibitor (PI), 0.5% α1-PI, and 100% fresh equine serum (ES) were used to treat pooled samples. Amount of latent and active MMP-2 and -9 was measured by optical density scanning of gelatin zymograms of treated and untreated tear samples. Results—Pooled tear samples obtained from ulcerated eyes contained the latent and active forms of MMP-2 and -9. Compared with MMP activity in untreated samples, total MMP...

Evaluation of various compounds to inhibit activity of matrix metalloproteinases in the tear film of horses with ulcerative keratitis

The primary objective of current treatment strategies for infectious keratitis is to sterilize the ulcer as rapidly as possible with topically administered antibiotics. Ulcerative processes can proceed in some cases, despite the absence of microbes, as a result of remaining corneal and tear film MMPs. Combining antibiotic therapy with MMP inhibitors can speed corneal healing, because MMPs play an important role in corneal ulceration and stromal liquefaction. MMPs from the rabbit, horse, and human being are inhibited by metal-binding agents EDTA, NAC, and doxycycline as well as by the serum antiprotease alpha2-macroglobulin. It is not yet certain which proteinase inhibitor has the most favorable therapeutic index for clinical use, although we prefer serum because of its effects on multiple types of proteinases. The MMP inhibitors do have significant therapeutic promise in the treatment of corneal ulceration.

Matrix metalloproteinase inhibition in corneal ulceration.

Chapter 4 – Diseases of the Cornea and Sclera

The cornea is composed of three layers: the outermost tear film and epithelium, the middle stroma, and the innermost endothelium The total thickness of the equine cornea is 08 to10 mm The normal equine corneal epithelium is approximately 60 lm thick The thickest corneal layer (700 lm), the stroma, is composed of a three-dimensional mosaic of interconnected keratocytes in an extracellular matrix (ECM) of proteoglycans and small-diameter collagen fibrils These fibrils are combined into highly ordered sheet-like lamellae that lie essentially parallel to the corneal surface The small consistent diameter of the stromal fibrils and their highly ordered spatial arrangement are partially responsible for corneal transparency The endothelium is a cellular monolayer with a thick collagenous basement membrane (Descemet’s membrane) Diseases of the equine corneal epithelium are covered in a separate article in this issue This review discusses the diagnosis and medical treatment of stromal keratomalacia or ‘‘melting ulcers,’’ stromal abscesses, eosinophilic keratitis (EK), and calcific band keratopathy These are common and important inflammatory keratopathies of the equine corneal stroma [1] Keratomalacia and stromal abscesses are associated with infection, leukocytic invasion of the stroma, and loss of tissue and tear film proteinase homeostasis Eosinophils infiltrate the stroma in response to unknown stimuli in EK Calcium is deposited in the stroma and epithelium secondary

https://www.vetequine.theclinics.com/article/S0749-0739(04)00025-2/pdf

Inflammatory stromal keratopathies: medical management of stromal keratomalacia, stromal abscesses, eosinophilic keratitis, and band keratopathy in the horse

Ulcerative keratitis is a common and potentially blinding ocular disease of horses, capable of progressing to corneal perforation in as little as 24 h. This rapid stromal degeneration is mediated in part by exogenous and endogenous proteinases. We measured and compared the concentrations of two matrix metalloproteinases (MMP-2 and MMP-9) and a serine proteinase (neutrophil elastase) present in the precorneal tear film of normal horses and horses with rapidly progressing ulcerative keratitis. Precorneal tear film samples were collected from 23 ulcerated and 21 unaffected eyes of 23 horses with unilateral ulcerative keratitis, and from 33 normal eyes of 17 control horses. MMP-2, MMP-9, and neutrophil elastase were identified by casein and gelatin zymography and quantified by computerized image analysis. Median MMP-9 levels were significantly higher in the precorneal tear film of young control horses vs. older control horses (P= 0.005). Median MMP-2, MMP-9, and neutrophil elastase levels were significantly higher in the precorneal tear film of ulcerated eyes when compared to age-matched normal controls (P= 0.004, P= 0.001, and P= 0.012, respectively). Median MMP-2 levels were also significantly higher in the precorneal tear film of contralateral eyes of affected horses when compared to age-matched normal controls (P= 0.004). No significant differences in median proteinase levels were detected between ‘sterile’ ulcers and those from which bacteria or mixed infections (bacteria and fungi) were isolated. However, median MMP-2 and neutrophil elastase levels were significantly higher in the precorneal tear film of eyes with ‘sterile’ ulcers when compared with ulcerated eyes from which fungi were isolated (P < 0.05). The results of this study support the use of topical antiproteinase therapy which targets both MMPs and serine proteinases in progressive equine ulcerative keratitis.

Evaluation of tear film proteinases in horses with ulcerative keratitis.

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Evaluation of tear film proteinases in horses with ulcerative keratitis.