Localization of TIMP-1, TIMP-2, TIMP-3, gelatinase A and gelatinase B in pathological human corneas

Kenney, M. Cristina; Chwa, Marilyn; Alba, Alicia Gaspar de; Saghizadeh, Mehrnoosh; Huang, Zhi-Shen; Brown, Donald J.

doi:10.1076/ceyr.17.3.238.5222

Cited by 71 publications

(58 citation statements)

References 44 publications

(53 reference statements)

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“…In keratoconus, stromal areas adjacent to regions where Bowman's layer was disrupted also stained for MDA. Because these regions are also associated with fibrosis (Kenney et al 1998(Kenney et al ,2000(Kenney et al ,2001, MDA staining may represent an association with fibrosis in the cornea.…”

Section: Malondialdehyde (Mda)mentioning

confidence: 99%

Evidence of Oxidative Stress in Human Corneal Diseases

Buddi

Lin

Atilano

et al. 2002

J Histochem Cytochem.

325

229

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S U M M A R YThis study localized malondialdehyde (MDA, a toxic byproduct of lipid peroxidation), nitrotyrosine [NT, a cytotoxic byproduct of nitric oxide (NO)], and nitric oxide synthase isomers (NOS) in normal and diseased human corneas. Normal corneas ( n ϭ 11) and those with clinical and histopathological diagnoses of keratoconus ( n ϭ 26), bullous keratopathy ( n ϭ 17), and Fuchs' endothelial dystrophy ( n ϭ 12) were examined with antibodies specific for MDA, NT, eNOS (constitutive NOS), and iNOS (inducible NOS). Normal corneas showed little or no staining for MDA, NT, or iNOS, whereas eNOS was detected in the epithelium and endothelium. MDA was present in all disease groups, with each group displaying a distinct pattern of staining. NT was detected in all keratoconus and approximately one half of Fuchs' dystrophy corneas. iNOS and eNOS were evident in all the diseased corneas. Keratoconus corneas showed evidence of oxidative damage from cytotoxic byproducts generated by lipid peroxidation and the NO pathway. Bullous keratopathy corneas displayed byproducts of lipid peroxidation but not peroxynitrite (MDA but not NT). Conversely, Fuchs' dystrophy corneas displayed byproducts of peroxynitrite with little lipid peroxidation (NT ϾϾ MDA). These data suggest that oxidative damage occurs within each group of diseased corneas. However, each disease exhibits a distinctive profile, with only keratoconus showing prominent staining for both nitrotyrosine and MDA. These results suggest that keratoconus corneas do not process reactive oxygen species in a normal manner, which may play a major role in the pathogenesis of this disease.

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Section: Malondialdehyde (Mda)mentioning

confidence: 99%

Evidence of Oxidative Stress in Human Corneal Diseases

Buddi

Lin

Atilano

et al. 2002

J Histochem Cytochem.

325

229

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“…[1][2][3] In the normal cornea, only very low levels of MMP-2 are found as proenzyme. [4][5][6] After injury, and in response to the release of cytokines, several MMPs in the cornea are upregulated by transcription or activation. 7 Preformed MMP-9 (Gelatinase B) may also be released from the secretory granules of neutrophils recruited by any associated inflammation.…”

Section: Introductionmentioning

confidence: 99%

Matrix metalloproteinase distribution during early corneal wound healing

Mulholland¹,

Tuft²,

Khaw³

2004

Eye

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Aim To compare matrix metalloproteinase (MMP) localisation in anterior keratectomy (AK) and lamellar keratectomy (LK) wounds. Methods Wounds were produced in one eye of 24 rabbits. The AK wounds were made to approximately 120 mm in depth and then allowed to re-epithelialise. The LK wounds were of similar depth, but the anterior stroma and epithelium were replaced after a second deeper keratectomy had been performed. Immunohistochemistry was used to localise the MMP-1, -2, -3, and -9 at intervals from 4 h to 14 days following surgery. The contralateral eyes acted as controls.Results After an AK wound MMP-1 was present at the leading edge of migrating epithelium after 18 h, while MMP-2 and -9 were localised behind the advancing epithelial edge. The presence of these enzymes rapidly fell to low levels after epithelial closure. There was only faint MMP-3 localisation between days 3 and 7. After an LK wound, MMP-1, -3, and -9 were not detected in the stromal interface, but MMP-2 was present at all time points. Conclusions This study suggests that after an AK wound, MMP-1 is a key mediator of epithelial migration, while MMP-2 and -9, and to a lesser extent MMP-3, may participate in the remodelling of corneal stroma and the reformation of epithelial basement membrane. In contrast, an LK wound results in a much lower stimulus for MMP activation. The action of MMP-2 in stromal repair is thus partly independent of epithelial injury.

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“…More recently, studies with MMP mutant mice have confirmed that MMPs play an important role in promoting inflammation and immunity: overexpression of MMP-1 in lungs promotes a spontaneous emphysema-like response (6), MMP-12 loss attenuates macrophage migration and lung damage caused by cigarette smoke (27), MMP-7 participates in proteolytic activation of antibacterial defensins by epithelial cells (32) and chemoattraction of inflammatory cells to the lung (16), and MMP-3 loss diminishes T-cell-dependent delayed type hypersensitivity responses, while the loss of MMP-9 delays the resolution of those responses (30). TIMP expression has also been associated with a variety of infectious and noninfectious inflammatory conditions, including those affecting the eye (12,14,34), and TIMP-3 regulates tumor necrosis factor alpha (TNF-␣) production (18). Collectively, these data highlight varied and complex roles for components of the TIMP-MMP axis during immune and inflammatory responses; however, TIMPs have not been directly shown to regulate responses to infection.…”

mentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase 1 Regulates Resistance to Infection

et al. 2005

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Tissue inhibitor of metalloproteinase 1 (TIMP-1)-deficient mice are resistant to Pseudomonas aeruginosa corneal infections. Corneas healed completely in TIMP-1-deficient mice, and infections were cleared faster in TIMP-1-deficient mice than in wild-type littermates. Genetic suppression studies using matrix metalloproteinase (MMP)-deficient mice showed that MMP-9, MMP-3, and MMP-7 but not MMP-2 or MMP-12 are needed for resistance. Increased resistance was also seen during pulmonary infections. These results identify a novel pathway regulating infection resistance.Twenty-five matrix metalloproteinases (MMPs) comprise the major extracellular matrix-degrading activities in mammals. They can remodel matrix during development, tumor metastasis, and cell migration but have nonmatrix substrates as well. MMPs are inhibited posttranslationally by four tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3, and TIMP-4) and by ␣ 2 -macroglobulin (33).Many correlative studies have suggested that MMP production was associated with inflammation and that MMP inhibition had an anti-inflammatory effect (3-5, 21, 26, 29). More recently, studies with MMP mutant mice have confirmed that MMPs play an important role in promoting inflammation and immunity: overexpression of MMP-1 in lungs promotes a spontaneous emphysema-like response (6), MMP-12 loss attenuates macrophage migration and lung damage caused by cigarette smoke (27), MMP-7 participates in proteolytic activation of antibacterial defensins by epithelial cells (32) and chemoattraction of inflammatory cells to the lung (16), and MMP-3 loss diminishes T-cell-dependent delayed type hypersensitivity responses, while the loss of MMP-9 delays the resolution of those responses (30). TIMP expression has also been associated with a variety of infectious and noninfectious inflammatory conditions, including those affecting the eye (12, 14, 34), and TIMP-3 regulates tumor necrosis factor alpha (TNF-␣) production (18). Collectively, these data highlight varied and complex roles for components of the TIMP-MMP axis during immune and inflammatory responses; however, TIMPs have not been directly shown to regulate responses to infection. To study the role of TIMP-1 in inflammation and immunity and its possible involvement in other physiological processes, mice deficient in TIMP-1 were generated and evaluated for responses during corneal and pulmonary infections with Pseudomonas aeruginosa.Preparation of Timp1 mutant mice. A replacement vector (Fig. 1A) targeted to the Timp1 locus in embryonic stem (ES) cells (Fig. 1B) produced a null allele in mice (Fig. 1C). The replacement vector included a 3.3-kb NdeI to HindIII 5Ј arm; a 21-mer oligonucleotide (5Ј-CTGATCAGCTGACTCGAG G-3Ј) at an EcoRV site in the third coding exon that abolished the EcoRV site generating BamHI, BglII, and XhoI sites; a G418 drug resistance cassette at the XhoI site; and a TK marker. Electroporated ES clones were screened by Southern blot analysis with a 1,400-nucleotide HindIII-NdeI Timp1 5Ј fragment as a probe. Mu...

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Localization of TIMP-1, TIMP-2, TIMP-3, gelatinase A and gelatinase B in pathological human corneas

Cited by 71 publications

References 44 publications

Evidence of Oxidative Stress in Human Corneal Diseases

Evidence of Oxidative Stress in Human Corneal Diseases

Matrix metalloproteinase distribution during early corneal wound healing

Tissue Inhibitor of Metalloproteinase 1 Regulates Resistance to Infection

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