Abstract
Abnormal wound healing processes can result in hypertrophic scars and keloids. Transforming growth factor-β1 (TGF-β1) and hepatocyte growth factor/scatter factor (HGF/SF) are biphasic growth factor cytokines in physiologic and pathophysiologic conditions. Findings have shown TGF-β1 to be pivotal in the formation of keloid tissue. Therefore, neutralizing antibodies may allow wound healing without keloid formation. As reported, TGF-β1 is antagonized by HGF/SF. Some authors have reported that exogenous administration of HGF/SF prevented scar formation. Hence, this study targeted TGF-β1 and determined the levels of HGF/SF in fibroblast cell culture. Keloid tissue was taken from seven patients. Another seven patients with mature nonhypertrophic scar served as controls. All tissues were cultured, and fibroblast cultures were used for further experiments. The TGF-β1 antisense was administered at 3 and 6 μmol/ml, and HGF/SF levels were determined after 16, 24, and 48 h of incubation. The levels of HGF/SF showed significant differences after incubation with antisense oligonucleotides. The increasing antisense levels resulted in increased HGF/SF levels (up to 87.66 pg/ml after 48 h of incubation). In conclusion, targeting TGF-β1 resulted in significantly increased levels of HGF/SF. The clinical relevance could include the use of locally administered HGF/SF in protein or gene form to minimize formation of keloids. Nevertheless, wound healing is the result of many interacting cytokines, so neutralizing or targeting one protein could result in no significant effect.
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References
Medical Data International (1998) U.S. markets for wound management products. Medical Data International, Irvine, CA
Hunt TK (1980) Disorders of wound healing. World J Surg 4:271–277
Tonnesen MG, Feng X, Clark RA (2000) Angiogenesis in wound healing. J Investig Dermatol Symp Proc 5:40–46
Ferguson MW, Whitby DJ, Shah M, Armstrong J, Siebert JW, Longaker MT (1996) Scar formation: The spectral nature of fetal and adult wound repair. Plast Reconstr Surg 97:854–860
Koonin AJ (1964) The aetiology of keloids: A review of the literature and a new hypothesis. S Afr Med J 38:913–916
Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH (1986) Transforming growth factor type beta: Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83:4167–4171
Kamamoto F, Paggiaro AO, Rodas A, Herson MR, Mathor MB, Ferreira MC (2003) A wound contraction experimental model for studying keloids and wound-healing modulators. Artif Organs 27:701–705
Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E (2000) Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci USA 97:2626–2631
Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB (1981) New class of transforming growth factors potentiated by epidermal growth factor: Isolation from non-neoplastic tissues. Proc Natl Acad Sci USA 78:5339–5343
Anzano MA, Roberts AB, Smith JM, Sporn MB, De Larco JE (1983) Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type alpha and type beta transforming growth factors. Proc Natl Acad Sci USA 80:6264–6268
Kutty RK, Kutty G, Hooks JJ, Wiggert B, Nagineni CN (1995) Transforming growth factor-beta inhibits the cytokine-mediated expression of the inducible nitric oxide synthase mRNA in human retinal pigment epithelial cells. Biochem Biophys Res Commun 215:386–393
Yue J, Mulder KM (2001) Transforming growth factor-beta signal transduction in epithelial cells. Pharmacol Ther 91:1–34
Chattopadhyay N, Felt HJ, Godbole MM, Brown EM (2004) Transforming growth factor beta receptor family ligands inhibit hepatocyte growth factor synthesis and secretion from astrocytoma cells. Brain Res Mol Brain Res 121:146–150
Samuel W, Nagineni CN, Kutty RK, Parks WT, Gordon JS, Prouty SM, Hooks JJ, Wiggert B (2002) Transforming growth factor-beta regulates stearoyl coenzyme A desaturase expression through a SMAD-signaling pathway. J Biol Chem 277:59–66
Roberts AB, Wakefield LM (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 100:8621–8623
Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA (1991) Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251:802–804
Koli K, Saharinen J, Hyytiainen M, Penttinen C, Keski-Oja J (2001) Latency, activation, and binding proteins of TGF-beta. Microsc Res Tech 52:354–362
Khalil N (1999) TGF-beta: From latent to active. Microbes Infect 1:1255–1263
Gleizes PE, Munger JS, Nunes I, Harpel JG, Mazzieri R, Noguera I, Rifkin DB (1997) TGF-beta latency: Biological significance and mechanisms of activation. Stem Cells 15:190–197
Ribeiro SM, Poczatek M, Schultz-Cherry S, Villain M, Murphy-Ullrich JE (1999) The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta. J Biol Chem 274:13586–13593
Heldin CH, Miyazono K, ten Dijke P (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471
Kawabata M, Inoue H, Hanyu A, Imamura T, Miyazono K (1998) SMAD proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors. EMBO J 17:4056–4065
Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791
Dai C, Liu Y (2004) Hepatocyte growth factor antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing SMAD transcriptional corepressor TGIF. J Am Soc Nephrol 15:1402–1412
Nakamura T, Nawa K, Ichihara A, Kaise N, Nishino T (1987) Purification and subunit structure of hepatocyte growth factor from rat platelets. FEBS Lett 224:311–316
Defacque H, Piquemal D, Basset A, Marti J, Commes T (1999) Transforming growth factor-beta 1 is an autocrine mediator of U937 cell growth arrest and differentiation induced by vitamin D3 and retinoids. J Cell Physiol 178:109–119
Zhang X, Yang J, Li Y, Liu Y (2005) Both Sp1 and SMAD participate in mediating TGF-beta 1-induced HGF receptor expression in renal epithelial cells. Am J Physiol Renal Physiol 288:F16–F26
Bortz J, Lienert G, Boehnke K (2000) Verteilungsfreie Methoden in der Biostatistik. Springer Verlag, Berlin
Krummel TM, Michna BA, Thomas BL, Sporn MB, Nelson JM, Salzberg AM, Cohen IK, Diegelmann RF (1988) Transforming growth factor beta (TGF-beta) induces fibrosis in a fetal wound model. J Pediatr Surg 23:647–652
Shah M, Foreman DM, Ferguson MW (1992) Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta. Lancet 339:213–214
Naim R, Sadick H, Bayerl C, Riedel F, Schafer C, Bran G, Hormann K (2005) Hepatocyte growth factor/scatter factor induces VEGF in human external auditory canal cholesteatoma cell culture. Int J Mol Med 15:67–71
Ito W, Kanehiro A, Matsumoto K, Hirano A, Ono K, Maruyama H, Kataoka M, Nakamura T, Gelfand EW, Tanimoto M (2005) Hepatocyte growth factor attenuates airway hyperresponsiveness, inflammation, and remodeling. Am J Respir Cell Mol Biol 32:268–280
Ono I, Yamashita T, Hida T, Jin HY, Ito Y, Hamada H, Akasaka Y, Ishii T, Jimbow K (2004) Local administration of hepatocyte growth factor gene enhances the regeneration of dermis in acute incisional wounds. J Surg Res 120:47–55
Naim R, Shen T, Riedel F, Bran G, Sadick H, Hormann K (2005) Regulation of apoptosis in external auditory canal cholesteatoma by hepatocyte growth factor/scatter factor. ORL J Otorhinolaryngol Relat Spec 67:45–50
Messadi DV, Le A, Berg S, Jewett A, Wen Z, Kelly P, Bertolami CN (1999) Expression of apoptosis-associated genes by human dermal scar fibroblasts. Wound Repair Regen 7:511–517
Nagata M, Takenaka H, Shibagaki R, Kishimoto S (1999) Apoptosis and p53 protein expression increase in the process of burn wound healing in guinea-pig skin. Br J Dermatol 140:829–838
Akasaka Y, Ishikawa Y, Ono I, Fujita K, Masuda T, Asuwa N, Inuzuka K, Kiguchi H, Ishii T (2000) Enhanced expression of caspase-3 in hypertrophic scars and keloid: Induction of caspase-3 and apoptosis in keloid fibroblasts in vitro. Lab Invest 80:345–357
Akasaka Y, Fujita K, Ishikawa Y, Asuwa N, Inuzuka K, Ishihara M, Ito M, Masuda T, Akishima Y, Zhang L, Ito K, Ishii T (2001) Detection of apoptosis in keloids and a comparative study on apoptosis between keloids, hypertrophic scars, normal healed flat scars, and dermatofibroma. Wound Repair Regen 9:501–506
Sato C, Tsuboi R, Shi CM, Rubin JS, Ogawa H (1995) Comparative study of hepatocyte growth factor/scatter factor and keratinocyte growth factor effects on human keratinocytes. J Invest Dermatol 104:958–963
Border WA, Ruoslahti E (1992) Transforming growth factor-beta in disease: The dark side of tissue repair. J Clin Invest 90:1–7
Shah M, Foreman DM, Ferguson MW (1994) Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci 107(Pt 5):1137–1157
Border WA, Ruoslahti E (1990) Transforming growth factor-beta 1 induces extracellular matrix formation in glomerulonephritis. Cell Differ Dev 32:425–431
Wahl SM, Allen JB, Costa GL, Wong HL, Dasch JR (1993) Reversal of acute and chronic synovial inflammation by antitransforming growth factor beta. J Exp Med 177:225–230
Beck LS, Deguzman L, Lee WP, Xu Y, McFatridge LA, Amento EP (1991) TGF-beta 1 accelerates wound healing: Reversal of steroid-impaired healing in rats and rabbits. Growth Factors 5:295–304
Pierce GF, Mustoe TA, Lingelbach J, Masakowski VR, Gramates P, Deuel TF (1989) Transforming growth factor beta reverses the glucocorticoid-induced wound-healing deficit in rats: Possible regulation in macrophages by platelet-derived growth factor. Proc Natl Acad Sci USA 86:2229–2233
Bernstein EF, Harisiadis L, Salomon G, Norton J, Sollberg S, Uitto J, Glatstein E, Glass J, Talbot T, Russo A (1991) Transforming growth factor-beta improves healing of radiation-impaired wounds. J Invest Dermatol 97:430–434
Fujiwara M, Muragaki Y, Ooshima A (2005) Upregulation of transforming growth factor-beta 1 and vascular endothelial growth factor in cultured keloid fibroblasts: Relevance to angiogenic activity. Arch Dermatol Res 297:161–169
Le AD, Zhang Q, Wu Y, Messadi DV, Akhondzadeh A, Nguyen AL, Aghaloo TL, Kelly AP, Bertolami CN (2004) Elevated vascular endothelial growth factor in keloids: Relevance to tissue fibrosis. Cells Tissues Organs 176:87–94
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Naim, R., Naumann, A., Barnes, J. et al. Transforming Growth Factor-β1-Antisense Modulates the Expression of Hepatocyte Growth Factor/Scatter Factor in Keloid Fibroblast Cell Culture. Aesth Plast Surg 32, 346–352 (2008). https://doi.org/10.1007/s00266-007-9078-6
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DOI: https://doi.org/10.1007/s00266-007-9078-6