Inhibition of Corneal Fibrosis by Topical Application of Blocking Antibodies to TGF?? in the Rabbit

Jester, James V.; Barry-Lane, Patricia A.; Petroll, Walter M; Olsen, David R.; Cavanagh, Harrison D

doi:10.1097/00003226-199703000-00010

Cited by 163 publications

(130 citation statements)

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“…However, growth in IGF-II was less than that in TGF-β, a growth factor known to cause the keratocytes to become myofibroblasts (Jester et al 1997). This is consistent with previous work (Musselmann et al 2003) that showed growth in extract is less than that in fetal bovine serum, another agent known to cause keratocytes to become fibroblasts/myofibroblasts.…”

Section: Discussionsupporting

confidence: 91%

“…The ability of IGF-II to stimulate proliferation of keratocytes in culture was compared to that of the TGF-β1 isoform (TGF-β), a mitogen previously shown to stimulate keratocyte proliferation and to be present in the stroma during wound healing (Jester et al 1997). Keratocytes were cultured in medium containing IGF-II, TGF-β or IGF-II plus TGF-β beginning on day 1.…”

Section: Resultsmentioning

confidence: 99%

“…We propose that the IGF-II present in the corneal stroma provides a reservoir mechanism in a non-vascular tissue to immediately activate keratocytes after corneal wounding and to ameliorate the scaring effects of TGF-β, a growth factor shown to be present in the cornea after wounding (Jester et al 1997). Chromatography of stromal extract on a column of Sephacryl S-300.…”

Section: Discussionmentioning

confidence: 99%

“…Antibodies to TGF-β have been shown to reduce keratocyte activation in corneal wounds (Jester et al 1997) and this suggests that TGF-β is present in wounds and activates keratocytes in vivo as well.…”

Section: Introductionmentioning

confidence: 99%

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IGF-II is present in bovine corneal stroma and activates keratocytes to proliferate in vitro

Musselmann

Kane

Alexandrou

et al. 2008

Experimental Eye Research

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Extracts of bovine corneal stroma have been shown to activate keratocytes in culture to proliferate. We fractionated stromal extract on a column of Sephacryl S-300 and tested the fractions for mitogenic activity using cell culture and for the presence of IGF-II and its binding protein IGFBP-2 by Western blot. We found that the mitogenic activity in the extract separated into major and minor peaks and that immunologically detectable IGF-II and IGFBP-2 co-eluted with the minor peak. We also compared the effects of 10 ng IGF-II/ml on keratocytes in culture to that of 2 ng TGF-β/ml over a 7-day culture period. We found that IGF-II and TGF-β, alone or combined, increased both 3 Hthymidine incorporation and DNA content of the cultures. The phenotype of the cells was determined by using antibodies to α-SM (smooth muscle) actin, fibronectin, SPARC, lumican and keratocan in Western blots of cell layers of media. Keratocytes cultured in IGF-II expressed no α-SM actin or fibronectin, low levels of SPARC and high levels of lumican and keratocan, indicating a native phenotype. Keratocytes in TGF-β expressed α-SM actin, fibronectin, SPARC and lumican, and expressed no or low levels of keratocan, indicating a myofibroblast phenotype. Keratocytes cultured in IGF-II plus TGF-β, however, expressed α-SM actin. fibronectin. SPARC, lumican, and keratocan by day 7 of culture. The results of this study show that IGF-II to be present in the corneal stroma, to stimulate keratocyte proliferation while maintaining native phenotype and to override the TGF-β mediated down regulation of keratocan production. The IGF-II in the stroma may serve as a mechanism to immediately activate keratocytes upon wounding and to ameliorate the scarring effects of TGF-β.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IGF-II is present in bovine corneal stroma and activates keratocytes to proliferate in vitro

Musselmann

Kane

Alexandrou

et al. 2008

Experimental Eye Research

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“…49,50 There have been several studies of myofibroblast differentiation in response to photorefractive keratectomy (PRK) in which anti-TGF␤ antibodies have been applied directly to the ocular surface of rabbits or cats. According to the results, blocking TGF␤ signaling after PRK reduced corneal haze 51,52 and enhanced optical quality. 53 Although the efficacy of anti-TGF␤ therapy has been demonstrated in animals and related pharmaceutical approaches to the treatment of IPF are close to clinical trial, 54 an ideal antifibrotic therapeutic candidate has yet to be identified.…”

Section: Discussionmentioning

confidence: 96%

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Lehmann

Xia

Kulkarni

et al. 2011

The American Journal of Pathology

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Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-␤1 (TGF␤1). In this study, we demonstrate that TGF␤1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1=H-indole-3=-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGF␤1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGF␤1-driven myofibroblast differentiation in AhR ؊/؊ fibroblasts: Its ability to inhibit TGF␤1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent.

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Disruption of anterior segment development by TGF‐β1 overexpression in the eyes of transgenic mice

Flügel-Koch

Ohlmann

Piatigorsky

et al. 2002

Developmental Dynamics

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Previous experiments showed that transgenic mice expressing a secreted selfactivating transforming growth factor (TGF) -␤1 did not show a phenotype in the lens and cornea until postnatal day 21, when anterior subcapsular cataracts, sporadic thickening of the corneal stroma, and thinning of the corneal epithelium were noted (Srinivasan et al., 1998). To examine the effects of higher concentrations of TGF-␤1 on the lens and cornea, we constructed transgenic mice harboring the strong, lens-specific chicken ␤B1-crystallin promoter driving an activated porcine TGF-␤1 gene. In contrast to the earlier study, the transgenic mice had microphthalmic eyes with closed eyelids. Already at embryonic day (E) 13.5, the future cornea of the transgenic mice was threefold thicker than that of wild-type littermates due to increased proliferation of corneal stromal mesenchyme cells. Staining of fibronectin and thrombospondin-1 was increased in periocular mesenchyme. At E17.5, the thickened transgenic corneal stroma was vascularized and densely populated by abundant star-shaped, neural cell adhesion molecule-positive cells of mesenchymal appearance surrounded by irregular swirls of collagen and extracellular matrix. The corneal endothelium, anterior chamber, and stroma of iris/ciliary body did not develop, and the transgenic cornea was opaque. Fibronectin, perlecan, and thrombospondin-1 were elevated, whereas type VI collagen decreased in the transgenic corneal stroma. Stromal mesenchyme cells expressed ␣-smooth muscle actin as did lens epithelial cells and cells of the retinal pigmented epithelium. By E17.5, lens fiber cells underwent apoptotic cell death that was followed by apoptosis of the entire anterior lens epithelium between E18.5 and birth. Posteriorly, the vitreous humor was essentially absent; however, the retina appeared relatively normal. Thus, excess TGF-␤1, a mitogen for embryonic corneal mesenchyme, severely disrupts corneal and lens differentiation. Our findings profoundly contrast with the mild eye phenotype observed with presumably lower levels of ectopic TGF-␤ and illustrate the complexity of TGF-␤ utilization and the importance of dose when assessing the effects of this growth factor.

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Inhibition of Corneal Fibrosis by Topical Application of Blocking Antibodies to TGF?? in the Rabbit

Cited by 163 publications

References 0 publications

IGF-II is present in bovine corneal stroma and activates keratocytes to proliferate in vitro

IGF-II is present in bovine corneal stroma and activates keratocytes to proliferate in vitro

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Disruption of anterior segment development by TGF‐β1 overexpression in the eyes of transgenic mice

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