Direct evidence for spatial and temporal regulation of transforming growth factor ?1 expression during cutaneous wound healing (original) (raw)
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Role of Elevated Plasma Transforming Growth Factor-β1 Levels in Wound Healing
The American Journal of Pathology, 1999
Transforming growth factor (TGF)-1 plays a central role in wound healing. Wounds treated with neutralizing antibody to TGF-1 have a lower inflammatory response , reduced early extracellular matrix deposition , and reduced later cutaneous scarring , indicating the importance of local tissue TGF-1. By contrast, increasing the local , tissue levels of TGF-1 increases the early extracellular matrix deposition but does not alter scar formation. Increased levels of plasma TGF-1 correlate with increased fibrogenesis in the lung , kidneys , and liver. The aim of the present study was to investigate the role of elevated systemic levels of TGF-1 on wound healing. We used transgenic mice that express high levels of active TGF-1 and have elevated plasma levels of TGF-1 and wild-type mice of the same strain as controls. Incisional wounds and subcutaneously implanted polyvinyl alcohol (PVA) sponges were analyzed. Surprisingly, cutaneous wounds in transgenic , TGF-1-overexpressing mice healed with reduced scarring accompanied by an increase in the immunostaining for TGF-3 and TGF--receptor RII and a decrease in immunostaining for TGF-1 compared with wounds in control mice. By contrast , the PVA sponges showed the opposite response , with PVA sponges from transgenic mice demonstrating an enhanced rate of cellular influx and matrix deposition into the sponges accompanied by an increase in the immunostaining for all three TGF- isoforms and their receptors compared with PVA sponges from control mice. Together , the data demonstrate that increased circulating levels of TGF-1 do not always result in increased expression or activity in selected target tissues such as the skin. The two wound models , subcutaneously implanted PVA sponges and cutaneous incisional wounds , differ significantly in terms of host response patterns. Finally, the data reinforce our previous observations that the relative ratios of the three TGF- isoforms is critical for control of scarring. M. Shah was supported by a travel grant from the Wellcome Trust.
Veterinary Surgery, 2002
Objective-To describe the localization of immunoreactive transforming growth factor (TGF)-1 in both normal skin and full-thickness dermal wounds of the limb and the thorax of the horse. Study Design-Six full-thickness excisional wounds were created on the lateral aspect of one metacarpal region and on the midthoracic area of each horse. Sequentially collected tissue specimens from wound margins were assessed for TGF-1 expression by immunohistochemistry. Animals-Four horses (2 to 4 years of age). Methods-A neutralizing monoclonal anti-human TGF-1 antibody was used to detect the spatial expression of TGF-1 protein by immunohistochemical localization in biopsies obtained before wounding and at 12 and 24 hours, and 5, 10, and 14 days. Results-No differences in localization of immunoreactive TGF-1 were detected between limb and thorax, for either intact skin or wounds. Unwounded epidermis stained moderately for TGF-1 protein throughout all layers, whereas the dermis was relatively devoid of immunoreactivity. During the acute stage of repair, migrating epithelium lost its stain, whereas cells of epidermal appendages remained strongly immunoreactive. The epithelium recovered its TGF-1 immunoreactivity during wound remodeling, although cells of the stratum corneum remained negative. Macrophages of the inflammatory exudate had positive cytoplasmic staining that diminished with time. Immunoreactivity of granulation tissue fibroblasts was evident early on and increased throughout the repair process. Conclusions-TGF-1 is constitutively expressed in normal, unwounded equine epithelium. Its expression is upregulated within the skin on injury and is associated with the cells involved in wound repair. Clinical Relevance-A more precise understanding of the temporal and spatial expression of TGF-1 during wound repair in horses should provide the groundwork for possible future manipulations of both normal and aberrant tissue repair.
Impaired cutaneous wound healing in transforming growth factor-β inducible early gene1 knockout mice
Wound Repair and Regeneration, 2012
Transforming growth factor-b inducible early gene (TIEG) is induced by transforming growth factor-b (TGF-b) and acts as the primary response gene in the TGF-b/ Smad pathway. TGF-b is a multifunctional growth factor that affects dermal wound healing; however, the mechanism of how TGF-b affects wound healing is still not well understood because of the complexity of its function and signaling pathways. We hypothesize that TIEG may play a role in dermal wound healing, with involvement in wound closure, contraction, and reepithelialization. In this study, we have shown that TIEG1 knockout (TIEG1-/-) mice have a delay in wound closure related to an impairment in wound contraction, granulation tissue formation, collagen synthesis, and reepithelialization. We also found that Smad7 was increased in the wounds and appeared to play a role in this wound healing model in TIEG1-/mice.
Neutralising antibody to TGF-β1,2 reduces cutaneous scarring in adult rodents
Journal of Cell Science, 1994
Scarring is a major cause of many clinical problems. Scar tissue interferes with growth, impairs function and is aesthetically unpleasant. However, scarring does not appear to be a problem of embryonic life. Embryonic wounds heal with a lower inflammatory and angiogenic response and have a different growth factor profile compared to adult wounds. We have used neutralising antibody to transforming growth factor-β1,2(TGF-β1,2) to alter the growth factor profile of cutaneous wounds in adult rodents and studied the effect on scar tissue formation. This paper extends our preliminary report that neutralising antibody to TGF-β reduces cutaneous scarring in adult rodents. To be effective, the neutralising antibody to TGF-β needs to be administered at the time of wounding or soon thereafter. The antiscarring effects of this neutralising antibody to TGF-β were dose dependent. Exogenous addition of neutralising antibody to TGF-β to incisional wounds reduced the inflammatory and angiogenic resp...
Growth factors and cytokines in wound healing
Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF-b) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), interleu-kin (IL) family, and tumor nerosis factor-a family. Currently, patients are treated by three growth factors: PDGF-BB, bFGF, and GM-CSF. Only PDGF-BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.
Dynamics of Transforming Growth Factor Beta Signaling in Wound Healing and Scarring
Advances in wound care, 2013
Wound healing is an intricate biological process in which the skin, or any other tissue, repairs itself after injury. Normal wound healing relies on the appropriate levels of cytokines and growth factors to ensure that cellular responses are mediated in a coordinated manner. Among the many growth factors studied in the context of wound healing, transforming growth factor beta (TGF-β) is thought to have the broadest spectrum of effects. Many of the molecular mechanisms underlying the TGF-β/Smad signaling pathway have been elucidated, and the role of TGF-β in wound healing has been well characterized. Targeting the TGF-β signaling pathway using therapeutic agents to improve wound healing and/or reduce scarring has been successful in pre-clinical studies. Although TGF-β isoforms (β1, β2, β3) signal through the same cell surface receptors, they display distinct functions during wound healing in vivo through mechanisms that have not been fully elucidated. The challenge of translating pre...
Journal of Clinical Investigation, 1989
Several growth factors are potential mediators of wound healing, although their actual roles, interactions, and therapeutic use are not established. Six well-characterized human growth factors were chosen for detailed investigation by topical application to standardized skin wounds in swine: epidermal growth factor (EGF), transforming growth factors a and B (TGF-a and TGF-), fibroblast growth factor (FGF), insulin-like growth factor-I (IGF-I), and platelet-derived growth factor (PDGF). When applied singly in doses up to 1,500 ng, only TGF-$ produced a marked tissue response, as demonstrated by an increase in the new connective tissue volume, the collagen content and maturity, and increased angiogenesis. However, TGF-,8 enhanced inflammation and caused abnormal epithelial differentiation and decreased epithelial volume, the last reversed by addition of IGF-I. Recombinant PDGF-2 homodimer, if given in combination with recombinant IGF-I, caused a similar increase in the new connective tissue volume and collagen content and maturity, but without increased inflammation. In addition, this combination stimulated increased amounts of epithelium with normal differentiation. The synergy of PDGF-2 and IGF-I was optimal at a ratio of 2:1 by weight. Of the six individual factors and nine combinations tested, the combinations of PDGF-2 and IGF-I or PDGF-2 and TGF-a were the most potent stimulators of healing in the absence of increased inflammation.
Veterinary Surgery, 2002
Objective-To determine whether transforming growth factor (TGF)-1 and-3 expression differs between equine limb wounds healing normally and those healing with experimentally induced exuberant granulation tissue (EGT). Study Design-Six wounds were created on the lateral aspect of both metacarpi of each horse; one forelimb was untreated, and the other was bandaged to stimulate the development of EGT. Sequential wound biopsies allowed comparison of growth factor expression between the two types of wound. Animals-Four horses (2 to 4 years of age; 350 to 420 kg). Methods-Wounds were assessed grossly, histologically, and by enzyme-linked immunosorbent assay (ELISA) for TGF-1 and Ϫ3 expression at 12 and 24 hours and 2, 5, 10, and 14 days postoperatively. Results-Bandaged wounds developed EGT. In all wounds, TGF-1 peaked early and remained elevated at 14 days. Peak TGF-1 concentration was higher in wounds with EGT, but not significantly so. Expression of TGF-3 differed from TGF-1, with peak TGF-3 concentrations being delayed. Concentrations of TGF-3 were higher in wounds healing normally, but this difference was not significant. Conclusions-During both normal and exuberant wound repair, the expression of TGF-1 occurred earlier than TGF-3 expression. Wounds healing with EGT tended to have higher concentrations of fibrogenic TGF-1 and lower concentrations of antifibrotic TGF-3 than wounds healing normally, although these differences were not statistically significant. Clinical Relevance-This study suggests that the production of EGT in bandaged wounds may be related to increased expression of fibrogenic TGF-1 and decreased expression of antifibrotic TGF-3. Further investigation of the roles of TGF-1 and-3 may be important in understanding the molecular control of EGT in horses.