Effect of topical anti-transforming growth factor-β on corneal stromal haze after photorefractive keratectomy in rabbits

Thom, Steven B; Myers, Jonathan S.; Rapuano, Christopher J.; Eagle, Ralph C.; Siepser, Steven B.; Gomes, José Álvaro Pereira

doi:10.1016/s0886-3350(97)80110-1

Cited by 42 publications

(23 citation statements)

References 20 publications

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“…Our data demonstrate that the patterns of uPAR expression and cleavage are similar for cornea, liver, and lung, suggesting that uPAR-mediated myofibroblast regulation is not unique to the cornea. Because an abundance of myofibroblasts and fibrotic scarring is correlated with excessive levels of TGF␤1, several wound healing studies have investigated the potential of inhibiting TGF␤1 with reagents such as anti-TGF␤1 antibodies to reduce fibrosis (Shah et al, 1992;Jester et al, 1997;Thom et al, 1997;Moller-Pedersen et al, 1998). Although fibrosis is inhibited with anti-TGF␤1 antibodies, cell migration and proliferation are also inhibited (Carrington et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation

Bernstein¹,

Twining

Warejcka

et al. 2007

MBoC

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Fibroblasts migrate into and repopulate connective tissue wounds. At the wound edge, fibroblasts differentiate into myofibroblasts, and they promote wound closure. Regulated fibroblast-to-myofibroblast differentiation is critical for regenerative healing. Previous studies have focused on the role in fibroblasts of urokinase plasmingen activator/urokinase plasmingen activator receptor (uPA/uPAR), an extracellular protease system that promotes matrix remodeling, growth factor activation, and cell migration. Whereas fibroblasts have substantial uPA activity and uPAR expression, we discovered that cultured myofibroblasts eventually lost cell surface uPA/uPAR. This led us to investigate the relevance of uPA/uPAR activity to myofibroblast differentiation. We found that fibroblasts expressed increased amounts of full-length cell surface uPAR (D1D2D3) compared with myofibroblasts, which had reduced expression of D1D2D3 but increased expression of the truncated form of uPAR (D2D3) on their cell surface. Retaining full-length uPAR was found to be essential for regulating myofibroblast differentiation, because 1) protease inhibitors that prevented uPAR cleavage also prevented myofibroblast differentiation, and 2) overexpression of cDNA for a noncleavable form of uPAR inhibited myofibroblast differentiation. These data support a novel hypothesis that maintaining full-length uPAR on the cell surface regulates the fibroblast to myofibroblast transition and that down-regulation of uPAR is necessary for myofibroblast differentiation. INTRODUCTIONMyofibroblast differentiation from fibroblasts is a critical component of the healing process. Regenerative healing (without scarring) results from the successful execution of what have been characterized as three distinct phases of wound healing. In the first phase, fibroblasts that migrate into the wound secrete proteases, extracellular matrix (ECM) molecules, and growth factors. In the second phase, fibroblasts differentiate into nonmotile, wound-contracting myofibroblasts that also secrete ECM proteins and remodel the ECM (Jester et al., 1995;Mohan et al., 2003;Netto et al., 2005). In the third phase, after wound closure, myofibroblasts usually disappear by apoptosis (Desmouliere et al., 1995). Pathological states such as hypertrophic scars, liver cirrhosis, idiopathic lung fibrosis, and glomerulosclerosis are characterized by the persistence of myofibroblasts, which contribute to disease progression by overproduction of ECM and by excessive contraction (Desmouliere et al., 2003;Gabbiani, 2003).To better understand the molecular basis for the fibroblast to myofibroblast transition, we have focused on the role of the urokinase plasmingen activator (uPA) pathway during wound healing. uPA is an extracellular serine protease that binds to its receptor, uPAR, and generates plasmin from plasminogen at the cell-matrix interface. Plasmin is a broadspectrum protease that not only cleaves fibrin and other ECM proteins but also promotes cell migration by activating matrix-sequestered metallopr...

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Section: Discussionmentioning

confidence: 99%

Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation

Bernstein¹,

Twining

Warejcka

et al. 2007

MBoC

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“…Antibodies directed against human TGF-β2 have been proposed to treat development of haze after PRK (Thom et al, 1997), conjunctival scarring after glaucoma surgery (Cordeiro et al, 1999a), and were tested in Phase III clinical trials (Group et al, 2007). TGF-β3 has already been discussed in this review as a potential anti-fibrotic agent although this role is debated.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…TGF-β3 has already been discussed in this review as a potential anti-fibrotic agent although this role is debated. At least in the scarring response of mouse conjunctiva (Cordeiro et al, 1999b), in haze development after PRK (Thom et al, 1997) and in corneal endothelial transformation , all TGF-β isoforms were shown to act rather pro-than anti-fibrotic. Earlier studies comparing all three TGF-β isoforms suggested that the actions of TGF-β isoforms may differ between in vitro and in vivo experiments (Serini and Gabbiani, 1996).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Myofibroblasts

Hinz¹

2016

Experimental Eye Research

352

341

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Myofibroblasts are activated in response to tissue injury with the primary task to repair lost or damaged extracellular matrix. Enhanced collagen secretion and subsequent contraction - scarring - are part of the normal wound healing response and crucial to restore tissue integrity. Due to myofibroblasts ability to repair but not regenerate, accumulation of scar tissue is always associated with reduced organ performance. This is a fair price to pay by the body for not falling apart. Whereas myofibroblasts typically vanish after successful repair, dysregulation of the normal repair process can lead to persistent myofibroblast activation, for instance by chronic inflammation or mechanical stress in the tissue. Excessive repair leads to the accumulation of stiff collagenous ECM contractures - fibrosis - with dramatic consequences for organ function. The clinical need to terminate detrimental myofibroblast activities has stimulated researchers to answer a number of essential questions: where do myofibroblasts come from, what are the factors leading to their activation, how do we discriminate myofibroblasts from other cells, what is the molecular basis for their contractile activity, and how can we stop or at least control them? This article reviews the current state of the myofibroblast literature by emphasizing their role in ocular repair and fibrosis. It appears that although the eye is quite an extraordinary organ, ocular myofibroblasts behave or misbehave just like their siblings in other organs.

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“…Such inhibition needs to be selective because simultaneous inhibition of many growth factors involved in wound healing (TGF-â, PDGF, FGF, IGF-I, IGF-II, EGF), using suramin, has deleterious effects on healing (11). Anti-TGF-â strategies have been successful in reducing the excessive healing responses on a variety of different wounds within the body (5,46,53,108,124). Therefore, it follows that similar strategies could be successful in inhibiting the formation of a restenotic lesion following vascular injury.…”

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor‐β:A Promising Target for Anti‐Stenosis Therapy

Chamberlain

2001

Cardiovascular Drug Reviews

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Transforming growth factor-â (TGF-â) is the general name for a family of cytokines which have widespread effects on many aspects of growth and development. The TGF-â isoforms are produced by most cell types and exert a wide range of effects in a context-dependent autocrine, paracrine or endocrine fashion via interactions with distinct receptors on the cell surface. TGF-â is involved in the wound healing process and, thus plays a significant role in the formation of a restenotic lesion after percutaneous transluminal coronary angioplasty (PTCA) or stenting. Perhaps because of its wide-ranging effects, TGF-â is usually released from cells in a latent form, and its activation and signaling are complex. Manipulation of the TGF-â1, TGF-â2, and TGF-â3 isoforms by inhibiting their expression, activation, or signaling reduces scarring and fibrosis in animal models. However, to date, few have reached clinical trial. This review summarizes current knowledge on the activation and signaling of TGF-â, and focuses on the anti-TGF-â strategies which may lead to clinical applications in the prevention of restenosis following PTCA or stenting.

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Effect of topical anti-transforming growth factor-β on corneal stromal haze after photorefractive keratectomy in rabbits

Abstract: Topical anti-TGF-beta antibody reduced stromal haze after PRK in the rabbit model and may be clinically beneficial in humans.

Cited by 42 publications

References 20 publications

Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation

Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation

Myofibroblasts

Transforming Growth Factor‐β:A Promising Target for Anti‐Stenosis Therapy

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