Transforming growth factor β3 for the prevention of vocal fold scarring

Ohno, Satoshi; Hirano, Shigeru; Kanemaru, S.; Kitani, Yoshiharu; Kojima, Tsuyoshi; Ishikawa, Seiji; Mizuta, Masanobu; Tateya, Ichiro; Nakamura, Tatsuo; Ito, Juichi

doi:10.1002/lary.22389

Cited by 30 publications

(34 citation statements)

References 28 publications

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“…We also show that TGF-β3 is a less potent inducer of key profibrotic molecule expression and fibroblast-myofibroblast differentiation in human VFF, compared with TGF-β1 and TGF-β2; and that delivery of exogenous TGF-β3 during the acute injury phase modulates the inflammatory environment and reduces VFM scar formation in vivo . These findings corroborate and provide mechanistic support for a recent therapeutic trial using canine VFM (Ohno et al, 2012), as well as multiple reports in skin (Ferguson et al, 2009; McCollum et al, 2011; Shah et al, 1995; So et al, 2011), lip (Hosokawa et al, 2003) and OM (Ohno et al, 2011). …”

Section: Discussionsupporting

confidence: 88%

“…Specifically, TGF-β1 and TGF-β2 are associated with fibrotic healing in adult wounds, whereas TGF-β3 is associated with regenerative healing in fetal wounds (Ferguson and O’Kane, 2004; Occleston et al, 2011; Shah et al, 1995; Whitby and Ferguson, 1991). Delivery of recombinant or therapeutically mutated TGF-β3 at the time of injury has been shown to reduce scar formation in skin (Shah et al, 1995; Waddington et al, 2010), lip (Hosokawa et al, 2003), oral mucosa (OM) (Ohno et al, 2011) and VFM (Ohno et al, 2012) in preclinical models, and recombinant TGF-β3 has demonstrated safety and efficacy in phase I and II human clinical trials (Ferguson et al, 2009; McCollum et al, 2011; So et al, 2011). Despite these promising outcomes, the mechanism of TGF-β3 action following injury is unclear, particularly with respect to cross-tissue variation in scar formation.…”

Section: Introductionmentioning

confidence: 99%

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TGF-β3 modulates the inflammatory environment and reduces scar formation following vocal fold mucosal injury in rats

Chang

Kishimoto

Hasan

et al. 2013

Disease Models &Amp; Mechanisms

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Transforming growth factor (TGF)-β1 and TGF-β3 have been reported to exert differential effects on wound healing, and possibly even account for tissue-specific differences in scar formation. Scarring is particularly detrimental in the vocal fold mucosa (VFM), where destruction of the native extracellular matrix causes irreparable biomechanical changes and voice impairment. Here, in a series of in vitro and in vivo experiments, we identified differences in TGF-β1 and TGF-β3 transcription and immunolocalization to various cell subpopulations in naïve and injured rat VFM, compared with oral mucosa (which undergoes rapid healing with minimal scar) and skin (which typically heals with scar). Treatment of cultured human vocal fold fibroblasts with TGF-β3 resulted in less potent induction of profibrotic gene transcription, extracellular matrix synthesis and fibroblast-myofibroblast differentiation, compared with treatment with TGF-β1 and TGF-β2. Finally, delivery of exogenous TGF-β3 to rat VFM during the acute injury phase modulated the early inflammatory environment and reduced eventual scar formation. These experiments show that the TGF-β isoforms have distinct roles in VFM maintenance and repair, and that TGF-β3 redirects wound healing to improve VFM scar outcomes in vivo.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

TGF-β3 modulates the inflammatory environment and reduces scar formation following vocal fold mucosal injury in rats

Chang

Kishimoto

Hasan

et al. 2013

Disease Models &Amp; Mechanisms

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“…Before concluding that TGF-β3 is ineffective, some technical aspects need to be further addressed. Because TGF-β3’s mechanism of action is through its inhibition of TGF-β1 and TGF-β2, some investigators feel TGF-β3 should be administered before injury [17, 18] and sustained through the remodeling phase of healing [19]. The rationale is that the initial cascade of cytokines involved in wound healing and scarring are triggered immediately after injury and present until the healing process is complete [10, 18].…”

Section: Discussionmentioning

confidence: 99%

“…A more relevant factor may be the degree of involved surface area. This model creates a larger injured surface area than in other studies on dermal scars, vocal cord injury, and buccal mucosal injury [17, 18, 21]. Larger areas of injury lead to prolonged exposure of fibrotic cytokines.…”

Section: Discussionmentioning

confidence: 99%

Preliminary results of antiscarring therapy in the prevention of postendoscopic esophageal mucosectomy strictures

Schomisch

Cipriano

et al. 2013

Surg Endosc

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Background Esophageal endoscopic submucosal dissection (ESD) is an effective minimally invasive therapy for early esophageal cancer and high-grade Barrett dysplasia. However, esophageal stricture formation after circumferential or large ESD has limited its wide adoption. Mitomycin C (MMC), halofuginone (Hal), and transforming growth factor β3 (TGF-β3) exhibits antiscarring effects that may prevent post-ESD stricture formation. Methods Using endoscopic mucosectomy (EEM) technique, an 8- to 10-cm-long circumferential esophageal mucosal segment was excised in a porcine model. The site was either untreated (control, n = 6) or received 40 evenly distributed injections of antiscarring agent immediately and at weeks 1 and 2. High and low doses were used: MMC 5 mg (n = 2), 0.5 mg (n = 2); Hal 5 mg (n = 2), 1.5 mg (n = 2), 0.5 mg (n = 2); TGF-β3 2 μg (n = 2), 0.5 μg (n = 2). The degree of stricture formation was determined by the percentage reduction of the esophageal lumen on weekly fluoroscopic examination. Animals were euthanized when strictures exceeded 80 % or the animals were unable to maintain weight. Results The control group had a luminal diameter reduction of 78.2 ± 10.9 % by 2 weeks and were euthanized by week 3. Compared at 2 weeks, the Hal group showed a decrease in mean stricture formation (68.4 % low dose, 57.7 % high dose), while both TGF-β3 dosage groups showed no significant change (65.3 % low dose, 76.2 % high dose). MMC was most effective in stricture prevention (53.6 % low dose, 35 % high dose). Of concern, the esophageal wall treated with high-dose MMC appeared to be necrotic and eventually led to perforation. In contrast, low dose MMC, TGF-β3 and Hal treated areas appeared re-epithelialized and healthy. Conclusions Preliminary data on MMC and Hal demonstrated promise in reducing esophageal stricture formation after EEM. More animal data are needed to perform adequate statistical analysis in order to determine overall efficacy of antiscarring therapy.

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“…The use of TGF-β3 has also been effectively tested in animal models, where it was found to reduce fibrosis and scarring by decreasing TGF-β1/2 levels (Shah et al, 1995; O'Kane and Ferguson 1997; Ohno et al, 2012; Chang et al, 2013). However, similar to the clinical challenges observed with TGF-β1 and 2 specific antibodies, no significant mitigation of scar development could be observed with TGF-β3 in an international Phase III clinical trial (Renovo, 2011).…”

Section: Possibilities For Therapeutic Interventionmentioning

confidence: 99%

Mechanotransduction and fibrosis

Duscher

Maan

Wong

et al. 2014

Journal of Biomechanics

162

146

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Scarring and tissue fibrosis represent a significant source of morbidity in the United States. Despite considerable research focused on elucidating the mechanisms underlying cutaneous scar formation, effective clinical therapies are still in the early stages of development. A thorough understanding of the various signaling pathways involved is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Mechanotransduction, which refers to the mechanisms by which mechanical forces are converted to biochemical stimuli, has been closely linked to inflammation and fibrosis and is believed to play a critical role in scarring. This review provides an overview of our current understanding of the mechanisms underlying scar formation, with an emphasis on the relationship between mechanotransduction pathways and their therapeutic implications.

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Transforming growth factor β3 for the prevention of vocal fold scarring

Abstract: Administration of TGFβ3 before injury significantly suppressed scar formation and induced favorable restoration of extracellular matrices in the vocal fold lamina propria, resulting in much improved phonatory function.

Cited by 30 publications

References 28 publications

TGF-β3 modulates the inflammatory environment and reduces scar formation following vocal fold mucosal injury in rats

TGF-β3 modulates the inflammatory environment and reduces scar formation following vocal fold mucosal injury in rats

Preliminary results of antiscarring therapy in the prevention of postendoscopic esophageal mucosectomy strictures

Mechanotransduction and fibrosis

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