Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue collagenases have been implicated in corneal ulceration in human corneal disease and in ulceration of the rabbit cornea that has served as a model system. Such enzymes from the rabbit and human cornea are inhibited by metal-binding agents of the EDTA type, by thiols, and by the human serum antiprotease alpha2-macroglobulin. Determination of the relative efficacies of collagenase inhibitors indicates that EDTA and Ca-EDTA are about one hundred times more effective on a molar basis than L-cysteine and its derivatives, N-acetyl-L-cysteine and D-penicillamine. The alpha2-macroglobulin on a molar basis, is superior as an inhibitor to the metal-binding agents and thiols. Although Ca may be a necessary cofactor of the corneal collagenases, such a requirement has not been established unequivocally. Inhibition and isotope studies do indicate a requirement for Zn. Thiols are thought to inhibit corneal collagenases by binding to or removing an intrinsic metal cofactor (Zn), and/or possibly by reducing one or more disulfide bonds. Inhibition by both EDTA-type agents and thiols is largely reversible by dialysis. The human alpha2-macroglobulin appears to inhibit corneal colleagenases irreversibly by forming tight complexes with them. Ca-EDTA, cysteine, and acetylcysteine, given as eyedrops, are able to prevent or retard ulceration in the alkali-burned rabbit cornea. They appear to have some efficacy in the prevention of corneal ulceration in humans. EDTA-type compounds are quite stable under routine storage, while acetylcysteine is more stable than cysteine. EDTA is quite toxic and should not be used as eye medication. Ca-EDTA has a low toxicity, and cysteine and acetylcysteine have even lower toxicity. It is not yet certain which inhibitor has the most favorable therapeutic index for clinical use, or is the optimal mode of drug delivery known. However, the collagenase inhibitors seem to have therapeutic promise in the prevention of corneal ulceration.
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PMID:Collagenase inhibitors: rationale for their use in treating corneal ulceration. 5 40

Why the cornea ulcerates, in the sense of what goes awry, may be related to the trapping of wound healing in a phase of proteolytic debridement related to a persistent epithelial defect. The initial avascularity of the cornea makes it particularly vulnerable to proteolytic damage. Studies on the biochemistry and cell biology of corneal ulceration have indicated that sequential interactions occur which result in the generation of collagenase activity and the development of ulceration. It is likely that the interactions are susceptible to intervention; and it is thought that eventual, successful treatment of corneal ulceration will require a complex therapy, with interventions at multiple sites of regulation.
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PMID:Regulation of collagenase. Therapeutic considerations. 8 26

Gross, light microscopic, and electron microscopic examination of the rabbit corneal destruction produced by experimental Pseudomonas aeruginosa infections revealed a combination of acute inflammation and liquefaction necrosis of the cornea. Degeneration of the epithelial cells and the start of polymorphonuclear leukocyte infiltration of the cornea occurred initially. These changes were followed by loss of the epithelium, degeneration and loss of the keratocytes and endothelium, loss of the characteristic weblike pattern of the proteoglycan ground substance, dispersal of ultrastructurally normal collagen fibrils, extensive accumulation followed by degeneration of polymorphonuclear leukocytes, and accumulation of plasma proteins and fibrin in the necrotic cornea. Histochemical examination of the cornea suggested a loss of the proteoglycan ground substance but not of collagen. Rabbit corneas injected with Clostridium histolyticum collagenase showed gross and cellular changes similar to those observed during the pseudomonal infections; however, histochemical examination suggested a loss of collagen, and electron microscopy revealed ultrastructurally abnormal collagen fibrils. The results support the idea (i) that a bacterial or host-derived collagenase is not required for extensive corneal damage during a P. aeruginosa corneal infection, and (ii) that a P. aeruginosa corneal infection may severly damage the cornea by producing extensive corneal edema and by causing the loss of the corneal proteoglycan ground substance, thus resulting in dispersal of undamaged collagen fibrils, weakening of the cornea, and subsequent descemetocele formation and corneal perforation by the anterior chamber pressure.
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PMID:Rabbit corneal damage produced by Pseudomonas aeruginosa infection. 16 2

1. Enzymes that may contribute to liquefaction of the cornea in retinol-deficient animals and in man have been studied using rat cornea. The established technique of culturing tissue fragments and determining the activity of collagenase (EC 3-4-24-3) and other enzymes in the medium after different periods of culture was used. 2. A collagenolytic system was detected in the media from cultures of rat corneas. This system probably consists of at least two enzymes, a collagenase and a neutral proteinase. 3. Both proteolytic and specific collagenolytic activity were greater in media from retinol-deficient rat corneas. The hydroxyproline level increased in parallel with the increase in enzyme activity. 4. In the final stages of retinol deficiency the cornea is invaded by granulocytes and other cells of the blood and we suggest that destruction of cornea collagen may be due largely to the activity of the enzymes from these cells.
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PMID:Collagenase and other proteinases in the cornea of the retinol-deficient rat. 16 77

The influence of a 1M CaCl2 extract and of a collagenase digest of corneal stroma of the biosynthesis of the macromolecules of corneal stroma was investigated. Calf corneas were incubated "in vitro" with radioactive tracers (14C-L-proline; 3H-D-glucosamine or 35SO4) in the presence or absence of the above extracts. After incubation the corneas are submitted to a fractional extraction in order to separate the major macromolecular fractions of the stroma. An increase in incorporation of all tracers is observed in the 1M CaCl2 (CTC), TCA and urea-extracts (containing resp. the diffusible macromolecules, proteoglycans, polymeric collagen and structural glycoproteins) in the presence of the macromolecular extracts and also with the collagenase-hydrolysate of cornea. These results show the existence of a stimulation of the biosynthesis of intracellular matrix macromolecules of the cornea by corneal extracts, probably through positive "feedback" type of mechanism.
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PMID:[Regulation of the biosynthesis of macromolecules of the intercellular corneal matrix]. 17 27

An experimental apparatus, which uses freshly collected, nondenatured rat tail tendons as substrate against crude corneal collagenase from alkali-burned rabbit corneas and clostridiopeptidase A, is introduced. The apparatus makes it possible to compare the collagenolytic activity of the two enzymes directly on intact connective tissue similar to intact corneal tissue. It was found that the two enzymes were able to reduce the tensile strength of rat tail tendons to less than 100 g in less than 5 h. The two enzymes attacked the tendons in structurally the same manner, estimated from a statistical model. The conclusion drawn is that crude corneal collagenase can degradate intact connective tissue indicating that it can attack the intact cornea.
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PMID:Collagenolysis of rat tail tendons by crude corneal collagenase and clostridiopeptidase A. 18 Aug 47

In the course of healing of experimental ulcer one could observe a distinct difference between a cornea, subjected to the action of glycerol and a control one. The damage to the chemical structure of collagenous fibers was much smaller than in the control. On the basis of the investigations performed one may conclude that glycerol, through dehydration of the corneal tissue and stimulation of mucopolysaccharide synthesis, suppresses the activity of collagenase. In polarized light this process was manifested by the double refraction phenomenon and in clinical observation--by an accelerated healing of ulcer.
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PMID:Effect of dehydration of the cornea with experimentally induced ulcer on collagenase activity. 18 91

Besides EDTA and cysteine, cystine and penicillamine are the best collagenase inhibitors. The collagenase is produced by the leucocytes. The action mechanism of the collagenase inhibitors is due to the chelation of Zn ions. The best clinical indications for collagenase inhibitors are punctate epithelial keratitis, chemical burns, recurrent corneal erosions in keratoconus, trophic postinfectious ulcerations of the cornea (metaherpetic ulcers), and descemetoceles.
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PMID:The Seventh Frederick H. Verhoeff Lecture. Collagenase and collagenase inhibitors. 20 98

Mixtures of epithelial and stromal cells isolated from normal adult rabbit cornea, when cocultured in the presence of cytochalasin B, produced latent collagenase, whereas neither cell type alone, nor the mixture in the absence of this agent, did so. The enzyme, a characteristic animal collagenase, required proteolytic activation. The relative concentrations of epithelial and stromal cells had a profound effect on on collagenase production, the enzyme activity bieng directly proportional to the number of stromal cells but inversely proportional to the number of epithelial cells. The amount of enzyme released into the medium was also directly proportional to cytochalasin B concentration. Media conditioned by cytochalasin B-treated epithelial or stromal cells did not stimulate collagenase secretion by the other cell type. The data suggest direct cell contact or close proximity as the mode of productive interaction and tentatively identify the stromal cell as the source of enzyme and the epithelial cell as a stimulator.
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PMID:Regulation of corneal collagenase production: epithelial-stromal cell interactions. 21 49

Dexamethasone sodium phosphate was administered topically to one eye of rabbits with bilateral alkali corneal burns, and saline solution was administered to the contralateral eye. Topical steroids were also administered in animals with moderate corneal ulcers and were found to enhance the severity of ulceration when given during the second and third weeks following the burn. If the corticosteroids were given daily in the first six days or in the fourth and fifth weeks following the burn, they did not have an adverse effect on the cornea. Corticosteroids can be used intensively during the first week following an alkali burn, without increasing the risk of corneal melting. The mechanism for the enhancement of corneal ulceration is not a direct augmentation of collagenase activity, but probably involves the inhibition of repair processes.
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PMID:Effect of topical corticosteroids on ulceration in alkali-burned corneas. 21 63


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