The Temporal Effects of Anti-TGF-β1, 2, and 3 Monoclonal Antibody on Wound Healing and Hypertrophic Scar Formation

Lu, Leonard; Saulis, Alexandrina S.; Liu, W. Robert; Roy, Nakshatra K.; Chao, Jerry; Ledbetter, Steven; Mustoe, Thomas A.

doi:10.1016/j.jamcollsurg.2005.03.032

Cited by 162 publications

(124 citation statements)

References 32 publications

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“…All three mammalian isoforms of TGF-␤ have been shown to be fibrogenic and induce matrix proteins, such as fibronectin and collagen 49,62,65,66 critical to the newly forming dermis. However, TGF-␤3, but not the other isoforms, has been shown to be involved in collagen gel matrix contraction (to stimulate wound contraction), 67 mitogenic behavior of cells, 68 acceleration of wound healing with decreased scaring, 63,69 -71 induction of hyaluronan, an important component involved in neodermal formation, 71,72 and increasing the expression of the collagenases MMP2 and MMP9, temporally important in wound ECM remodeling.…”

Section: Discussionmentioning

confidence: 99%

Calreticulin Enhances Porcine Wound Repair by Diverse Biological Effects

Nanney

Woodrell

Greives

et al. 2008

The American Journal of Pathology

137

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Extracellular functions of the endoplasmic reticulum chaperone protein calreticulin (CRT) are emerging. Here we show novel roles for exogenous CRT in both cutaneous wound healing and diverse processes associated with repair. Compared with platelet-derived growth factor-BB-treated controls, topical application of CRT to porcine excisional wounds enhanced the rate of wound re-epithelialization. In both normal and steroid-impaired pigs, CRT increased granulation tissue formation. Immunohistochemical analyses of the wounds 5 and 10 days after injury revealed marked up-regulation of transforming growth factor-␤3 (a key regulator of wound healing), a threefold increase in macrophage influx, and an increase in the cellular proliferation of basal keratinocytes of the new epidermis and of cells of the neodermis. In vitro studies confirmed that CRT induced a greater than twofold increase in the cellular proliferation of primary human keratinocytes, fibroblasts, and microvascular endothelial cells (with 100 pg/ml, 100 ng/ ml, and 1.0 pg/ml, respectively). Moreover, using a scratch plate assay, CRT maximally induced the cellular migration of keratinocytes and fibroblasts (with 10 pg/ml and 1 ng/ml, respectively). In addition, CRT induced concentration-dependent migration of keratinocytes, fibroblasts macrophages, and monocytes in chamber assays. These in vitro bioactivities provide mechanistic support for the positive biological effects of CRT observed on both the epidermis and dermis of wounds in vivo, underscoring a significant role for

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Section: Discussionmentioning

confidence: 99%

Calreticulin Enhances Porcine Wound Repair by Diverse Biological Effects

Nanney

Woodrell

Greives

et al. 2008

The American Journal of Pathology

137

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“…Comparing the expression profiles of TGF-β1, -β2 and -β3 and their receptors in keloids, hypertrophic scar and normal skin derived fibroblasts, Bock and colleagues found significantly lower TGF-β2 mRNA expression in hypertrophic scar fibroblasts compared with fibroblasts derived from keloids and normal skin, while TGF-β3 mRNA expression was significantly lower in keloid fibroblasts in comparison with fibroblasts derived from hypertrophic scar and normal skin (44). Thus, specifically, beyond 1 week, differential expression of TGF-β isoforms, receptors and activity modulators, rather than the mere presence or absence of TGF-β, may have a major role in the development of both keloids and hypertrophic scarring (48).…”

Section: Fibrogenic Responsementioning

confidence: 92%

Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies

Gauglitz

Körting

Pavicic

et al. 2010

Mol Med

1,111

1,012

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Excessive scars form as a result of aberrations of physiologic wound healing and may arise following any insult to the deep dermis. By causing pain, pruritus and contractures, excessive scarring significantly affects the patient's quality of life, both physically and psychologically. Multiple studies on hypertrophic scar and keloid formation have been conducted for decades and have led to a plethora of therapeutic strategies to prevent or attenuate excessive scar formation. However, most therapeutic approaches remain clinically unsatisfactory, most likely owing to poor understanding of the complex mechanisms underlying the processes of scarring and wound contraction. In this review we summarize the current understanding of the pathophysiology underlying keloid and hypertrophic scar formation and discuss established treatments and novel therapeutic strategies.

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“…27,106 This work was expanded on by Mustoe's group, who investigated the effects of an anti-TGF-b1, 2, and 3 monoclonal antibody on wound healing and HTS formation in rabbit ear wounds. 108 They found that early treatment of the wounds (days 0, 2, and 4 postwounding) with a neutralizing antibody impaired wound healing without decreasing scar hypertrophy; whereas middle (days 7, 9, and 11) and late (days 11, 12, and 13) treatment of wounds significantly reduced scar hypertrophy. 108 CAT-192 is a human monoclonal antibody that neutralizes TGF-b1 and was shown to improve corneal wound healing in bovine organ cultures by promoting re-epithelialization.…”

Section: Strategies Used For Targeting the Tgf-b Signaling Pathway Tomentioning

confidence: 99%

“…108 They found that early treatment of the wounds (days 0, 2, and 4 postwounding) with a neutralizing antibody impaired wound healing without decreasing scar hypertrophy; whereas middle (days 7, 9, and 11) and late (days 11, 12, and 13) treatment of wounds significantly reduced scar hypertrophy. 108 CAT-192 is a human monoclonal antibody that neutralizes TGF-b1 and was shown to improve corneal wound healing in bovine organ cultures by promoting re-epithelialization. 139 Scleroderma, or systemic sclerosis (SSc), is a rare connective tissue disease that is characterized by autoimmunity, vasculopathy, and fibrosis (scarring) of the skin and internal organs.…”

Section: Strategies Used For Targeting the Tgf-b Signaling Pathway Tomentioning

confidence: 99%

“…108 They found that early treatment of the wounds (days 0, 2, and 4 post-wounding) with neutralizing antibody impaired wound healing without decreasing scar hypertrophy, whereas as middle (days 7, 9, and 11) and late (days 11, 12, and 13) treatment of wounds significantly reduced scar hypertrophy. 108 Although this study could not determine which TGF-b isoform(s) are involved, a follow-up study investigating the temporal expression of TGF-b isoforms in the rabbit ear model showed that elevated levels of TGF-b1, and possibly TGF-b2, are associated with HTS formation. 109 Another study using the rabbit ear model showed that viral delivery of a dominant negative (truncated) mutant of TbRII (to block endogenous TGF-b signaling) 8-12 days post-wounding decreased hypertrophic scarring.…”

mentioning

confidence: 99%

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