Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022568 (keratitis)
 5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The meta-herpetic keratitis is clinically characterized by the occurrence of a parenchymatous keratitis due to iterative herpetic corneal wounds. The rupture of the Bowman membrane which makes such a deep wound possible is performed by an enzyme: collagenase. This parenchymatous keratitis is rarely due to an extension of the viral infection. Most often it has an immunologic origin. It is a disciform keratitis due to a viral allergy, or a polymorphic keratitis connected with a bacterial, often tubercular, origin. In this case, one always notices a characteristic sugar tongs like composite limbic vascularization. Recovery can only be obtained by a specific desensitization.
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PMID:[Considerations on the meta-herpetic keratitis (author's transl)]. 20 62

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

This critical review is based upon controlled experimental and clinical data. Dendritic keratitis initially should be treated by debridement of the diseased epithelium followed by antiviral medication. The advantages and disadvantages of different debridement techniques and different synthetic antivirals are discussed. Rational treatment of other forms of herpetic eye disease with antivirals, steroids, therapeutic soft lenses, collagenase inhibitors etc. necessitates first of all an exact diagnosis (disciform edema, interstitial herpetic keratitis, herpetic (kerato-)uveitis, metaherpetic erosion, metaherpetic ulcer). Therapeutic or prophylactic measures which as yet have found no valid experimental or clinical basis are discussed as well as further developments. Special interest is laid upon the application of human interferon.
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PMID:[Herpes therapy and prophylaxis. I. A critical review (author's transl)]. 100 22

Four cases of human keratitis caused by the tropical fungus Lasiodiplodia theobromae have been encountered in Miami, Florida bringing to 8 the number of cases reported in the world literature. Two of the ulcers were mild. Three patients recovered without severe impairment of vision after topical polyene treatment, but 1 patient with a severe ulcer required therapeutic keratoplasty after 11 days of topical natamycin. Histopathology revealed fungus deep in the cornea, invading Descemet's membrane. L. theobromae appeared to have collagenase activity in vitro. Inoculation of L. theobromae into the corneas of rabbits produced progressive ulcers. The fungus was endemic in Miami on home grown and imported bananas. Polyene antimycotic antibiotics were fungicidal for L. theobromae in vitro. Thiabendazole was effectively fungistatic but varied in fungicidal effect. Clotrimazole and miconazole were only incompletely fungistatic. Of 7 strains of L. theobromae tested, 4 were relatively resistant to 5-flurocytosine.
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PMID:Lasiodiplodia theobromae as a cause of keratomycoses. 108 94

Collagen shields applied to the corneas of patients with bacterial keratitis degrade rapidly, often within a few hours. Once treatment brings the infection under control, subsequently applied collagen shields degrade more slowly. In vitro models were established to evaluate the significance of these observations. Twenty-four and 72-hour collagen shields were incubated with collagenase from Clostridium histolyticum. The in vitro rate of digestion of the shields was directly proportional to the concentration of collagenase, with the rate of digestion of the 24-hour shields being greater than that of the 72-hour shields. Therefore, the rate of collagen shield degradation may be a clinically useful index of collagenase activity on the ocular surface. Ultrastructural studies of collagen shields from patients with acute bacterial keratitis revealed irregular degradation of shield matrix with no evidence of adherence of microorganisms or inflammatory cells. Co-incubation of deepithelialized rabbit corneas and collagen shields resulted in inhibition of the digestion of the rabbit corneas when the weight:weight ratio of collagen shield:rabbit cornea was increased to greater than or equal to 2:1. Collagen shields may inhibit corneal collagen degradation in infectious ulceration and melting disorders by effectively competing for collagenase on the ocular surface.
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PMID:The collagen shield as a collagenase inhibitor and clinical indicator of collagenase activity on the ocular surface. 131 47

Pseudomonas aeruginosa elastase is a zinc metalloproteinase which is released during P. aeruginosa infections. Pseudomonas keratitis, which occurs following contact lens-induced corneal trauma, can lead to rapid, liquefactive necrosis of the cornea. This destruction has been attributed to the release of both host-derived enzymes and the bacterial products P. aeruginosa elastase, alkaline protease, exotoxin A, and lipopolysaccharide endotoxin. A synthetic metalloproteinase inhibitor, HSCH2 (DL)CH[CH2CH(CH3)2]CO-Phe-Ala-NH2, which we previously showed to be a potent inhibitor of corneal collagenase and alkali-induced corneal ulceration, was tested as a potential inhibitor of P. aeruginosa elastase. Inhibition constants (Kis) for the resolved diastereomers were determined with the chromogenic substrate furylacryloyl-glycyl-L-leucyl-L-alanine. One isomer had a Ki of 0.3 microM, while the other had a Ki of 0.4 microM. The more potent diastereomer was evaluated in vivo in experimentally induced Pseudomonas keratitis in rabbits. Following inoculation of one cornea of each rabbit, topical treatment with a 1 mM solution of the inhibitor significantly delayed the onset of corneal melting and perforation, as compared with the results for the control and gentamicin-treated groups. This protective effect suggests that the inhibitor may have a therapeutic application by delaying the progression of corneal destruction in Pseudomonas keratitis.
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PMID:Inhibition of Pseudomonas aeruginosa elastase and Pseudomonas keratitis using a thiol-based peptide. 212 41

Axenic cultures of Acanthamoeba castellanii contained a collagenolytic enzyme that digested collagen shields and purified collagen in vitro. Specificity of biologic activity was determined by the addition of selected enzyme inhibitors to the assays and revealed that the parasite-conditioned medium contained both collagenase and lower concentrations of other proteolytic enzymes. However, most of the collagenolytic and pathogenic activity was directly attributable to specific collagenase. Intrastromal injection of sterile, Acanthamoeba-conditioned culture medium into naive Lewis rats produced corneal lesions clinically similar to and closely resembling those found in biopsy specimens of human patients diagnosed with acanthamoebic keratitis. Histopathologic analysis revealed moderate-to-severe neutrophil infiltration, disruption of stromal lamellae, and edema. Identical pathologic sequelae were produced by intrastromal injection of purified collagenase (25 units/ml). The pathogenicity of the soluble parasite-derived product was removed by passage over affinity columns armed with antibody specific for collagenase. These results indicated that soluble parasite-derived factors were capable of producing lesions characteristic of acanthamoebic keratitis and that the pathogenicity of these factors was either directly or indirectly attributable to specific collagenase activity.
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PMID:In vivo and in vitro collagenolytic activity of Acanthamoeba castellanii. 217 83

To get a better understanding of the possible role of proteases in the pathogenesis of fungal keratitis, the extracellular proteases of a clinical isolate of Aspergillus flavus, from a severe case of keratitis, were identified and partially characterized. This strain, designated CU226/88, was grown with a variety of substrates as nitrogen sources, under conditions that would be expected to derepress the production of extracellular proteases. When grown on minimal medium with milk protein as a nitrogen source, the fungus appeared to produce primarily a metalloprotease, which has a zinc cofactor. When grown with insoluble collagen or elastin as a nitrogen source, a serine protease and cysteine protease, as well as the metalloprotease, are produced. Strain CU226/88 can grow with collagen, but not elastin, as the sole source of carbon as well as nitrogen. It is possible that the collagenase activity is a mediator of the severe corneal destruction caused by this isolate.
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PMID:Extracellular proteases of Aspergillus flavus. Fungal keratitis, proteases, and pathogenesis. 217 95

The structural alterations elicited in the rabbit corneal stroma by experimental Serratia marcescens keratitis and by a highly purified serratia protease preparation were compared by gross observation, biochemical analyses, and electron microscopic examination of the affected tissue. Acute inflammation, liquefactive necrosis of the cornea, and descemetocele formation occurred during the development of the infection and after the intracorneal injection of submicrogram amounts of the protease. In vitro incubation of insoluble corneal stromal tissue with the bacterium or with the protease resulted in solubilization of the stromal proteoglycan ground substance; however, specific collagenase activity was not detected. Electron microscopic examination of corneas damaged by the bacterial infection and by the protease revealed loss of ruthenium red staining of the proteoglycan ground substance and dispersal of ultrastructurally normal collagen fibrils. Thus, our findings indicate that the major corneal damage which occurs during serratia keratitis and after the injection of the serratia protease is caused by solubilization and loss of the ground substance of the tissue. In addition, the observation that the major structural alterations observed during serratia keratitis can be reproduced by the bacterial protease supports the idea that the enzyme is involved, at least in part, with the production of severe corneal damage by the bacterium.
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PMID:Characterization of rabbit corneal damage produced by Serratia keratitis and by a serratia protease. 702 49

Sulfonylated L-valine hydroxamate derivatives were obtained by reaction of alkyl/arylsulfonyl halides with the title amino acid, followed by treatment with benzyl chloride, and conversion of the COOH moiety to the CONHOH group. Other derivatives were obtained by reaction of N-benzyl-L-valine with arylisocyanates, arylsulfonylisocyanates or benzoylisothiocyanate, followed by the similar conversion of the COOH into the CONHOH moiety, with hydroxylamine in the presence of carbodiimides. The obtained compounds were assayed as inhibitors of the Clostridium histolyticum collagenase, ChC (EC 3.4.24.3), a zinc enzyme which degrades triple helical collagen. The hydroxamate derivatives were generally 100-500 times more active than the corresponding carboxylates. In the series of synthesized derivatives, substitution patterns leading to best ChC inhibitors were those involving perfluoroalkylsulfonyl- and substituted-arylsulfonyl moieties, such as pentafluorophenylsulfonyl; 3- and 4-protected-aminophenylsulfonyl-; 3- and 4-carboxyphenylsulfonyl-; 3-trifluoromethylphenylsulfonyl; or 1- and 2-naphthyl among others. Similarly to the matrix metalloproteinase hydroxamate inhibitors, ChC inhibitors of the type reported here must incorporate hydrophobic moieties at the P(2') and P(3') subsites, in order to achieve tight binding to the enzyme. Such compounds might lead to drugs useful in the treatment corneal bacterial keratitis.
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PMID:Protease inhibitors. Part 7. Inhibition of Clostridium histolyticum collagenase with sulfonylated derivatives of L-valine hydroxamate. 1069 84


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