Matrix Metalloproteinase Inhibition Modulates Postoperative Scarring after Experimental Glaucoma Filtration Surgery

Wong, Tina; Mead, Anna; Khaw, PT

doi:10.1167/iovs.02-0366

Cited by 98 publications

(80 citation statements)

References 34 publications

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“…35 Broadspectrum inhibition of MMP activity has reduced matrix contraction and collagen production in vitro 35 and in an animal model of glaucoma surgery. 38 On the other hand, the profibrotic mediator IL-13, which is present in the stromal tissues of ocular MMP, 26 causes a reduction in MMP-3 synthesis by both normal and pemphigoid conjunctival fibroblasts, so whether the effect of IL-13 overrides the inherent behavior of pemphigoid fibroblasts with regard to MMP-3 synthesis in vivo is yet to be determined. MMP-13 (collagenase-3) digests collagens I, II, III, IV, gelatin, fibronectin, and proteoglycans.…”

Section: Discussionmentioning

confidence: 99%

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Saw

Schmidt

Offiah

et al. 2011

The American Journal of Pathology

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Ocular mucous membrane pemphigoid is an immunobullous disease in which excessive conjunctival fibrosis causes blindness, and the pathogenesis of scarring is incompletely understood. To establish whether profibrotic fibroblasts with an altered phenotype exist in ocular mucous membrane pemphigoid, we compared the functional characteristics of pemphigoid conjunctival fibroblasts to normal conjunctival fibroblasts with respect to cell division; migration; collagen contraction; matrix metalloproteinase, secretion of collagen and chemokines; and myofibroblast differentiation. We found that pemphigoid fibroblasts showed increased cell division (P ‫؍‬ 0.01), increased migration in serum-free medium (72 ؎ 18 migrated cells versus 33 ؎ 11, P ‫؍‬ 0.04), increased collagen contraction in the presence of 10 ng/ml tumor necrosis factor-␣, increased collagen type I secretion (P ‫؍‬ 0.03), increased secretion of matrix metalloproteinase-3 (P ‫؍‬ 0.03), and increased secretion of eotaxin in response to interleukin-13 (P ‫؍‬ 0.04). Differences between pemphigoid and normal conjunctival fibroblasts with respect to collagen contraction and MMP secretion in the presence of interleukin-13 were also observed. Together, these findings indicate that pemphigoid conjunctival fibroblasts have a profibrotic phenotype that is maintained in vitro. No differences between pemphigoid fibroblasts obtained from acutely inflamed versus clinically uninflamed conjunctiva were observed. Developing effective antifibrotic therapies will require understanding of the mechanisms that both induce and maintain the profibrotic phenotype.

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Section: Discussionmentioning

confidence: 99%

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Saw

Schmidt

Offiah

et al. 2011

The American Journal of Pathology

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“…A slit lamp microscope was used for observations of filtration blebs and depth of the anterior chamber, and complications were recorded. Blebs were evaluated on a qualitative scale of 1+ to 4+, based on the bleb's appearance, size, and vascularity, and documented as described [20,21] . The scores reflecting increasing bleb height and size were as follows: 1+, minimal height, conjunctiva thickening, and no microcysts; 2+, microcysts are present; 3+, elevated bleb covering 3 to 4 clock hours of the eye; and 4+, greatly elevated bleb covering more than 5 clock hours of Histological evaluation For light microscope analysis, animals were sacrificed on d 7, 14, 21, and 28 after filtration surgery.…”

Section: Recombination Adenovirus Assaysmentioning

confidence: 99%

Adenovirus-mediated delivery of p27KIP1 to prevent wound healing after experimental glaucoma filtration surgery

et al. 2009

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Aim:The aim of the study was to evaluate the outcome of adenovirus-mediated p27 KIP1 (Ad-p27) expression on wound healing after filtration surgery and to investigate the inhibition of cell proliferation induced by Ad-p27. Methods: We constructed the adenovirus recombinant vector Ad-p27 and administered it to a rabbit model of glaucoma filtration surgery by subconjunctival injection; phosphate-buffered saline (PBS) and mitomycin C (MMC) were used as controls. Intraocular pressure (IOP), bleb scores, and anterior chamber depths were observed during a 28-d period. Histological examinations, fluorescence observations and Western blot analyses were evaluated. Results: Ad-p27 enhanced the surgical outcome and inhibited cell proliferation when compared with PBS. Bleb scores in the Ad-p27-treated eyes were higher than those in the PBS-treated eyes on d 7 (P<0.01), 14 (P<0.01) and 21 (P<0.05). On d 28, IOP remained significantly decreased in the Ad-p27 group compared with the PBS group (P<0.05). However, no differences in bleb scores or IOPs were observed between the Ad-p27 and MMC groups. Histological analysis showed that total cell numbers were markedly reduced, and less scar tissue was observed at the surgical site in eyes treated with Ad-p27. The number of fibroblasts was decreased in Tenon's capsule in Ad-p27-treated eyes; however, a marked and diffuse signal from the green fluorescent protein (GFP) was observed in fibroblasts. Western blot analysis revealed a high level of p27 KIP1 expression in conjunctival epithelium (P<0.01), relatively high expression in superficial scleral stroma (P<0.01), and low expression in corneal epithelium in the Ad-p27 group. Conclusions: Ad-p27 administration significantly improves the outcome of filtration surgery and inhibits postoperative proliferation in rabbit eyes. These findings suggest that p27 KIP1 is a potential adjunctive agent for inhibition of wound healing after filtration surgery.

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“…These agents block different aspects of the wound healing cascade including the initial signaling events, 14,15 cell proliferation, 16 and cell migration. 17 Recently, antiproliferative gene therapy has been used adjunctively with glaucoma surgery in animal models. We used a recombinant adenovirus (rAd) to introduce the human gene for p21 WAF-1/cip-1 (p21) into rabbit Tenon's fibroblasts in a normotensive model of glaucoma surgery.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy using p21WAF-1/Cip-1 to modulate wound healing after glaucoma trabeculectomy surgery in a primate model of ocular hypertension

Heatley

Kiland

Faha³

et al. 2004

Gene Ther

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Matrix Metalloproteinase Inhibition Modulates Postoperative Scarring after Experimental Glaucoma Filtration Surgery

Cited by 98 publications

References 34 publications

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Adenovirus-mediated delivery of p27KIP1 to prevent wound healing after experimental glaucoma filtration surgery

Gene therapy using p21WAF-1/Cip-1 to modulate wound healing after glaucoma trabeculectomy surgery in a primate model of ocular hypertension

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