Protective effects of matrix metalloproteinase-12 following corneal injury (original) (raw)

Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury

The American journal of pathology, 1996

Delayed re-epithelialization of the cornea after injury usually precedes stromal ukceration. Previous findings using a rat thermal injury model suggested that re-epithelialization is impeded by products of resident corneal cells, which destroy adbesive structures at the basement membrane zone. In this study, we provide additional evidencefor this concept. Failure to re-epithelialize was found to correlate with an increase in the amounts of gelatinolytic matrix metalloproteinases present in the rat cornea. One of these gelatinases, gelatinase B, is synthesized by the resident corneal cells, and inhibition of its synthesis correlated with inhibition of basement membrane dissolution. The matrix metalloproteinases collagenase and stromelysin are also synthesized by resident corneal cells in thermaly injured corneas of rabbits, but the timing of bulk enzyme synthesis correlated more closely with deposition of repair tissue in the stroma than with failure to re-epithelialize. Nevertheless, in human corneas with repair defects, gelatinase B and collagenase are synthesized by cells in the basal layer of the epithelium directly adjacent to the basement membrane, suggesting that both couldparticipate in dissolution ofthis structure. Importantly, treatment of thermally injured corneas with a synthetic inhibitor of matrix metalloproteinases significantly improved basement membrane integrity. These data support the concept that over-expression of matrix metalloproteinases by resident corneal cells impedes re-epithelialization after some types ofcorneal injury. (Am J Pathol 1996, 149:1287-1302 Corneal ulceration is a devastating disorder that can cause blindness. Ulcers manifest as a breakdown of the collagenous stromal tissue, a process that was once thought to be a simple physical dissolution described as corneal melting. A major change in our understanding of stromal ulceration occurred when this process was shown to be associated with the secretion of type collagen-degrading enzymes from living cells.' In organ culture, collagenolytic activity was shown to be produced by superficial sections of ulcerating cornea containing the epithelial layer and a small amount of anterior stroma. However, the observation that neutrophil infiltration is a hallmark of stromal ulceration suggested that these cells (with their accumulated stores of hydrolytic enzymes) might provide the more important source of collagenase. Experiments showing that chemical injuries do not ulcerate in animals that have been made neutropenic have provided support for this hypothesis.2

Temporal and spatial expression of matrix metalloproteinases during wound healing of human corneal tissue

Experimental eye research, 2003

Following a myocardial infarction (MI), the homeostatic balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is disrupted as part of the left ventricle (LV) response to injury. The full complement of responses to MI has been termed LV remodeling and includes changes in LV size, shape and function. The following events encompass the LV response to MI: 1) inflammation and LV wall thinning and dilation, 2) infarct expansion and necrotic myocyte resorption, 3) accumulation of fibroblasts and scar formation, and 4) endothelial cell activation and neovascularization.1 , 2 In this review, we will summarize MMP and TIMP roles during these events, focusing on the spatiotemporal localization and MMP and TIMP effects on cellular and tissue-level responses. We will review MMP and TIMP structure and function, and discuss specific MMP roles during both the acute and chronic phases post-MI, which may provide insight into novel therapeutic targets to limit adverse remodeling in the MI setting.

Matrix Metalloproteinase-8 Facilitates Neutrophil Migration through the Corneal Stromal Matrix by Collagen Degradation and Production of the Chemotactic Peptide Pro-Gly-Pro

The American Journal of Pathology, 2008

Matrix metalloproteinase (MMP)-8 and MMP-9 play several roles in inflammation, including degradation of extracellular matrix (ECM) components and regulation of cytokine activity. To determine the roles of MMP-8 and MMP-9 in a neutrophil-dependent inflammatory response, we used a murine model of corneal inflammation in which LPS is injected into the corneal stroma. In contrast to wild-type mice, we found that i) lipopolysaccharide (LPS)injected CXCR2 ؊/؊ corneas had impaired neutrophil infiltration and did not express either MMP-8 or MMP-9; ii) neutrophil migration through the central cornea was impaired in Mmp8 ؊/؊ , but not Mmp9 ؊/؊ , mice; iii) neutrophil migration was inhibited in collagenase-resistant mice; iv) the chemotactic Pro-Gly-Pro (PGP) tripeptide that binds CXCR2 was decreased in CXCR2 ؊/؊ mice; v) PGP production was impaired in Mmp8 ؊/؊ corneas; and vi) neutralizing anti-PGP antibody did not inhibit neutrophil infiltration in Mmp8 ؊/؊ mice. We found no effects of MMP-8 on LPS-induced CXC chemokine (LIX, or CXCL5)-induced neutrophil recruitment or on LPS-induced CXC chemokine production. Together, these studies indicate that neutrophils contribute to the production of both MMP-8 and MMP-9 in LPS-injected corneas and that MMP-8 regulates neutrophil migration through the dense collagenous ECM of the corneal stroma by generating chemotactic PGP dur-ing inflammation.

Cytokines and signaling pathways regulating matrix metalloproteinase-9 (MMP-9) expression in corneal epithelial cells

Journal of Cellular Physiology, 2009

Matrix metalloproteinase-9 (MMP-9) is a well known regulator and effecter of many cellular processes including wound healing. In the cornea, either too much or too little MMP-9 can be detrimental to overall wound repair. We investigated the secreted factors as well as the intracellular signaling pathways and the promoter sequences that mediate this regulation. Primary culture rabbit corneal epithelial cells were treated with various cytokines alone or in different combinations and MMP-9 induction was assessed by gel zymography. Pharmacological inhibitors were used to determine the intracellular signaling pathways induced by the cytokines tested and deletion promoter constructs were created to determine the regions of the MMP-9 promoter involved in the cytokine regulation, thereby assessing the exact transcription factors binding the MMP-9 promoter. We found that two cytokine families, TGF-β and IL-1, act additively in an isoform non-specific manner to induce MMP-9 in this cell type. Our data suggest TGF-β mediated MMP-9 induction may be regulated by the NF-kB, Smad3, and JNK pathways, whereas the IL-1β mediated induction may be regulated by the NF-kB and p38 pathways. Inhibition of the p38, NF-kB, or JNK pathways significantly reduced, but did not abrogate, basal MMP-9 levels. Inhibition of the ERK pathway did not have an effect on MMP-9 mediated expression in either the treated or untreated co-transfected cells.

Downregulation of Matrix Metalloproteinase-2 in Corneal Fibroblasts by Interleukin-1 Receptor Antagonist Released from Corneal Epithelial Cells

Investigative Ophthalmology & Visual Science, 2010

The authors previously showed that the expression of various junctional proteins in corneal epithelial cells or corneal fibroblasts (CFs) is regulated by the presence of the other cell type in a coculture system. In this study, the effect of corneal epithelial cells on the expression of matrix metalloproteinases (MMPs) in CFs was studied. Human CFs and simian virus 40-transformed human corneal epithelial (HCE) cells were cultured on opposite sides of a collagen vitrigel membrane. Expression of MMPs in CFs was examined by reverse transcription-polymerase chain reaction and immunoblot analyses. The amounts of MMP-2 mRNA and protein in CFs were decreased by the presence of HCE cells. HCE cells had no effect on the expression of MMP-1 in CFs. HCE cells released interleukin (IL)-1 receptor antagonist (IL-1RA) into the culture medium, and depletion of IL-1RA in HCE cells by RNA interference largely abolished the effect of these cells on MMP-2 expression in CFs. The downregulation of MMP-2 expression in CFs by HCE cells was blocked by an inhibitor of signaling by the mitogen-activated protein kinase (MAPK) ERK (PD98059) but was not affected by those of signaling by the MAPKs p38 (SB203580) or JNK (SP600125). Corneal epithelial cells downregulated expression of MMP-2 in CFs in a manner dependent at least in part on the release of IL-1RA from the former cells. This effect might contribute to the attenuation of corneal stromal remodeling by corneal epithelial cells.

Matrix metalloproteinase inhibition in corneal ulceration

Veterinary Clinics of North America: Small Animal Practice, 2004

The cornea and precorneal tear film combine to function as a strong refractive lens. To produce such an optically powerful structure, the corneal microanatomy consists of an epithelium and thin epithelial basement membrane, a thick relatively acellular stroma, Descemet's membrane, and a monolayered endothelium.

MMPs in the eye: emerging roles for matrix metalloproteinases in ocular physiology

Progress in Retinal and Eye Research, 2002

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that function to maintain and remodel tissue architecture. Their substrates represent an astounding variety of extracellular matrix components, secreted cytokines and cell surface molecules, and they have been implicated in a wide range of processes and diseases. To date MMPs have been found in virtually every tissue of the eye under conditions of health and disease. Although their functions in vivo remain poorly understood, it is clear they impact on essentially every aspect of eye physiology. This chapter reviews the expanding literature on MMPs in the eye and attempts to place it in the context of basic MMP biology. A general overview of MMP functions is presented first, and then the discussion moves to examples of possible MMP roles in two eye structures. For the cornea, we present recent work on the roles of MMPs during various aspects of wound healing. For the retina, we describe the activities of MMPs in specific disease states from which common principles may emerge. r

Macrophage Metalloelastase (MMP-12) Deficiency Mitigates Retinal Inflammation and Pathological Angiogenesis in Ischemic Retinopathy

PLoS ONE, 2012

Pathological angiogenesis is a major cause of vision loss in ischemic and inflammatory retinal diseases. Recent evidence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in inflammation, tissue remodeling and angiogenesis. However, little is known about the role of MMP-12 in retinal pathophysiology. The present study aims to explore the enzyme's contributions to retinal angiogenesis in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice. We find that MMP-12 expression was upregulated in OIR, accompanied by elevated macrophage infiltration and increased inflammatory markers. Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule and inflammatory cytokines and reduced vascular leakage in OIR. Concomitantly, these mice had markedly reduced macrophage content in the retina with impaired macrophage migratory capacity. Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR and mitigated pathological retinal neovascularization (NV). Similar results were observed in the study using MMP408, a pharmacological inhibitor of MMP-12. Intriguingly, in contrast to reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina in OIR. Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and inflammation, contributing to retinal vascular dysfunction and pathological angiogenesis.