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The molecular mechanism of hypertrophic scar

Journal of Cell Communication and Signaling Aims and scope

Abstract

Hypertrophic scar (HTS) is a dermal form of fibroproliferative disorder which often develops after thermal or traumatic injury to the deep regions of the skin and is characterized by excessive deposition and alterations in morphology of collagen and other extracellular matrix (ECM) proteins. HTS are cosmetically disfiguring and can cause functional problems that often recur despite surgical attempts to remove or improve the scars. In this review, the roles of various fibrotic and anti-fibrotic molecules are discussed in order to improve our understanding of the molecular mechanism of the pathogenesis of HTS. These molecules include growth factors, cytokines, ECM molecules, and proteolytic enzymes. By exploring the mechanisms of this form of dermal fibrosis, we seek to provide some insight into this form of dermal fibrosis that may allow clinicians to improve treatment and prevention in the future.

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Abbreviations

ALK 1:

activin-receptor-like kinase 1

ALK 5:

activin-receptor-like kinase 5

α-SMA:

alpha smooth muscle actin

COL1:

type I collagen

COL1A2:

collagen type I α2

COL3:

type III collagen

COL4:

type IV collagen

Co-SMAD:

common mediator Smad

CTGF:

connective tissue growth factor

ECM:

extracellular matrix

ERK:

extracellular signal-regulated kinase

HTS:

hypertrophic scar

IGF-1:

insulin-like growth factor-1

IL:

interleukin

IFN:

interferon

I-SMAD:

inhibitory Smad

JNK:

c-Jun N-terminal kinase

LSP-1:

leukocyte specific protein-1

LTBP:

latent TGF-β1 binding protein

M6P/IGF II-R:

Mannose 6-phosphate/insulin-like growth factor II receptors

MAPK:

mitogen-activated protein kinase

MCP-1:

monocyte chemotactic protein-1

MMP:

matrix metalloproteinase

PKB:

protein kinase B

R-Smad:

receptor-regulated Smad

SDF-1:

stromal cell-derived factor-1

SIP1:

Smad interacting protein 1

SLRP:

small leucine-rich proteoglycan

TGF:

transforming growth factor

TGF-βR:

TGF-β receptor

TIEG1:

TGF-β inducible early gene 1

TIMP:

tissue inhibitor of metalloproteinases

References

  • Abe R, Donnelly SC, Peng T, Bucala R, Metz CN (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 15;166(12):7556–7562

    Google Scholar 

  • Ahn ST, Monafo WW, Mustoe TA (1989) Topical silicone gel: a new treatment for hypertrophic scars. Surgery 106(4):781–786, discussion 786–7

    CAS  PubMed  Google Scholar 

  • Ali-Bahar M, Bauer B, Tredget EE, Ghahary A (2004) Dermal fibroblasts from different layers of human skin are heterogeneous in expression of collagenase and types I and III procollagen mRNA. Wound Repair Regen 12(2):175–182

    PubMed  Google Scholar 

  • Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 15;116(Pt 2):217–224

    Google Scholar 

  • Anzarut A, Olson J, Singh P, Rowe BH, Tredget EE (2009) The effectiveness of pressure garment therapy for the prevention of abnormal scarring after burn injury: a meta-analysis. J Plast Reconstr Aesthet Surg 62(1):77–84, Epub 2008 Jan 14

    PubMed  Google Scholar 

  • Armour A, Scott PG, Tredget EE (2007) Cellular and molecular pathology of HTS: basis for treatment. Wound Repair Regen 15(Suppl 1):S6–S17

    PubMed  Google Scholar 

  • Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1(5):260–266

    CAS  PubMed  Google Scholar 

  • Atiyeh BS (2007) Nonsurgical management of hypertrophic scars: evidence-based therapies, standard practices, and emerging methods. Aesthetic Plast Surg 31(5):468–492, discussion 493–4. Epub 2007 Jun 18

    PubMed  Google Scholar 

  • Atiyeh BS, Costagliola M, Hayek SN (2005) Keloid or hypertrophic scar: the controversy: review of the literature. Ann Plast Surg 54(6):676–680

    CAS  PubMed  Google Scholar 

  • Avniel S, Arik Z, Maly A, Sagie A, Basst HB, Yahana MD, Weiss ID, Pal B, Wald O, Ad-El D, Fujii N, Arenzana-Seisdedos F, Jung S, Galun E, Gur E, Peled A (2006) Involvement of the CXCL12/CXCR4 pathway in the recovery of skin following burns. J Invest Dermatol 126(2):468–476

    CAS  PubMed  Google Scholar 

  • Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4(7):540–550

    CAS  PubMed  Google Scholar 

  • Bauer BS, Tredget EE, Marcoux Y, Scott PG, Ghahary A (2002) Latent and active transforming growth factor beta1 released from genetically modified keratinocytes modulates extracellular matrix expression by dermal fibroblasts in a coculture system. J Invest Dermatol 119(2):456–463

    CAS  PubMed  Google Scholar 

  • Bock O, Yu H, Zitron S, Bayat A, Ferguson MW, Mrowietz U (2005) Studies of transforming growth factors beta 1–3 and their receptors I and II in fibroblast of keloids and hypertrophic scars. Acta Derm Venereol 85(3):216–220

    CAS  PubMed  Google Scholar 

  • Bombaro KM, Engrav LH, Carrougher GJ, Wiechman SA, Faucher L, Costa BA, Heimbach DM, Rivara FP, Honari S (2003) What is the prevalence of hypertrophic scarring following burns? Burns 29(4):299–302

    PubMed  Google Scholar 

  • Bonniaud P, Kolb M, Galt T, Robertson J, Robbins C, Stampfli M, Lavery C, Margetts PJ, Roberts AB, Gauldie J (2004) Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis. J Immunol 173(3):2099–2108

    CAS  PubMed  Google Scholar 

  • Broekelmann TJ, Limper AH, Colby TV, McDonald JA (1991) Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci U S A 1;88(15):6642–6646

    Google Scholar 

  • Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A (1994) Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1(1):71–81

    CAS  PubMed Central  PubMed  Google Scholar 

  • Castagnoli C, Stella M, Magliacani G (2002) Role of T-lymphocytes and cytokines in post-burn hypertrophic scars. Wound Repair Regen 10(2):107–108

    PubMed  Google Scholar 

  • Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T (2003) Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 253(1–2):269–285

    CAS  PubMed  Google Scholar 

  • Chan T, Ghahary A, Demare J, Yang L, Iwashina T, Scott PG, Tredget EE (2002) Development, characterization, and wound healing of the keratin 14 promoted transforming growth factor-beta1 transgenic mouse. Wound Repair Regen 10(3):177–187

    PubMed  Google Scholar 

  • Chesney J, Bacher M, Bender A, Bucala R (1997) The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci U S A 10;94(12):6307–6412

    Google Scholar 

  • Choi WT, An J (2011) Biology and clinical relevance of chemokines and chemokine receptors CXCR4 and CCR5 in human diseases. Exp Biol Med (Maywood) 236(6):637–647, Epub 2011 May 12

    CAS  Google Scholar 

  • Craig MJ, Loberg RD (2006) CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases. Cancer Metastasis Rev 25(4):611–619

    CAS  PubMed  Google Scholar 

  • Cutroneo KR (2007) TGF-beta-induced fibrosis and SMAD signaling: oligo decoys as natural therapeutics for inhibition of tissue fibrosis and scarring. Wound Repair Regen 15(Suppl 1):S54–S60

    PubMed  Google Scholar 

  • Dang CM, Beanes SR, Lee H, Zhang X, Soo C, Ting K (2003) Scarless fetal wounds are associated with an increased matrix metalloproteinase-to-tissue-derived inhibitor of metalloproteinase ratio. Plast Reconstr Surg 111(7):2273–2285

    PubMed  Google Scholar 

  • Darzi MA, Chowdri NA, Kaul SK, Khan M (1992) Evaluation of various methods of treating keloids and hypertrophic scars: a 10-year follow-up study. Br J Plast Surg 45(5):374–379

    CAS  PubMed  Google Scholar 

  • Das S, Mandal M, Chakraborti T, Mandal A, Chakraborti S (2003) Structure and evolutionary aspects of matrix metalloproteinases: a brief overview. Mol Cell Biochem 253(1–2):31–40

    CAS  PubMed  Google Scholar 

  • Davis PA, Corless DJ, Aspinall R, Wastell C (2001) Effect of CD4(+) and CD8(+) cell depletion on wound healing. Br J Surg 88(2):298–304

    CAS  PubMed  Google Scholar 

  • De Felice B, Garbi C, Santoriello M, Santillo A, Wilson RR (2009) Differential apoptosis markers in human keloids and hypertrophic scars fibroblasts. Mol Cell Biochem 327(1–2):191–201

    CAS  PubMed  Google Scholar 

  • Desmoulière A, Geinoz A, Gabbiani F, Gabbiani G (1993) Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122(1):103–111

    PubMed  Google Scholar 

  • Ding J, Hori K, Zhang R, Marcoux Y, Honardoust D, Shankowsky HA, Tredget EE (2011) Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 in the formation of postburn hypertrophic scar (HTS). Wound Repair Regen 19(5):568–578

    PubMed  Google Scholar 

  • Doucet C, Brouty-Boyé D, Pottin-Clémenceau C, Canonica GW, Jasmin C, Azzarone B (1998) Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma. J Clin Invest 101(10):2129–2139

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dunkin CS, Pleat JM, Gillespie PH, Tyler MP, Roberts AH, McGrouther DA (2007) Scarring occurs at a critical depth of skin injury: precise measurement in a graduated dermal scratch in human volunteers. Plast Reconstr Surg 119(6):1722–1732, discussion 1733–4

    CAS  PubMed  Google Scholar 

  • Engrav LH, Garner WL, Tredget EE (2007) Hypertrophic scar, wound contraction and hyper-hypopigmentation. J Burn Care Res 28(4):593–597

    PubMed  Google Scholar 

  • Eto H, Suga H, Aoi N, Kato H, Doi K, Kuno S, Tabata Y, Yoshimura K (2012) Therapeutic potential of fibroblast growth factor-2 for hypertrophic scars: upregulation of MMP-1 and HGF expression. Lab Invest 92(2):214–223. doi:10.1038/labinvest.2011.127, Epub 2011 Sep 26

    CAS  PubMed  Google Scholar 

  • Feldman SR, Trojanowska M, Smith EA, Leroy EC (1993) Differential responses of human papillary and reticular fibroblasts to growth factors. Am J Med Sci 305(4):203–207

    CAS  PubMed  Google Scholar 

  • Fernandez EJ, Lolis E (2002) Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol 42:469–499

    CAS  PubMed  Google Scholar 

  • Ferreira AM, Takagawa S, Fresco R, Zhu X, Varga J, DiPietro LA (2006) Diminished induction of skin fibrosis in mice with MCP-1 deficiency. J Invest Dermatol 126(8):1900–1908, Epub 2006 May 11

    CAS  PubMed  Google Scholar 

  • Ghahary A, Shen YJ, Nedelec B, Scott PG, Tredget EE (1995a) Interferons gamma and alpha-2b differentially regulate the expression of collagenase and tissue inhibitor of metalloproteinase-1 messenger RNA in human hypertrophic and normal dermal fibroblasts. Wound Repair Regen 3(2):176–184

    CAS  PubMed  Google Scholar 

  • Ghahary A, Shen YJ, Scott PG, Tredget EE (1995b) Immunolocalization of TGF-beta 1 in human hypertrophic scar and normal dermal tissues. Cytokine 7(2):184–190

    CAS  PubMed  Google Scholar 

  • Ghahary A, Shen YJ, Nedelec B, Wang R, Scott PG, Tredget EE (1996) Collagenase production is lower in post-burn hypertrophic scar fibroblasts than in normal fibroblasts and is reduced by insulin-like growth factor-1. J Invest Dermatol 106(3):476–481

    CAS  PubMed  Google Scholar 

  • Ghahary A, Shen Q, Shen YJ, Scott PG, Tredget EE (1998a) Induction of transforming growth factor beta 1 by insulin-like growth factor-1 in dermal fibroblasts. J Cell Physiol 174(3):301–309

    CAS  PubMed  Google Scholar 

  • Ghahary A, Tredget EE, Chang LJ, Scott PG, Shen Q (1998b) Genetically modified dermal keratinocytes express high levels of transforming growth factor-beta1. J Invest Dermatol 110(5):800–805

    CAS  PubMed  Google Scholar 

  • Ghahary A, Tredget EE, Mi L, Yang L (1999) Cellular response to latent TGF-beta1 is facilitated by insulin-like growth factor-II/mannose-6-phosphate receptors on MS-9 cells. Exp Cell Res 251(1):111–120

    CAS  PubMed  Google Scholar 

  • Ghahary A, Tredget EE, Shen Q, Kilani RT, Scott PG, Houle Y (2000) Mannose-6-phosphate/IGF-II receptors mediate the effects of IGF-1-induced latent transforming growth factor beta 1 on expression of type I collagen and collagenase in dermal fibroblasts. Growth Factors 17(3):167–176

    CAS  PubMed  Google Scholar 

  • Ghahary A, Tredget EE, Ghahary A, Bahar MA, Telasky C (2002) Cell proliferating effect of latent transforming growth factor-beta1 is cell membrane dependent. Wound Repair Regen 10(5):328–335

    PubMed  Google Scholar 

  • Ghahary A, Marcoux Y, Karimi-Busheri F, Li Y, Tredget EE, Kilani RT, Lam E, Weinfeld M (2005) Differentiated keratinocyte-releasable stratifin (14-3-3 sigma) stimulates MMP-1 expression in dermal fibroblasts. J Invest Dermatol 124(1):170–177

    CAS  PubMed  Google Scholar 

  • Gharaee-Kermani M, Denholm EM, Phan SH (1996) Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 271(30):17779–17784

    CAS  PubMed  Google Scholar 

  • Gold MH, Foster TD, Adair MA, Burlison K, Lewis T (2001) Prevention of hypertrophic scars and keloids by the prophylactic use of topical silicone gel sheets following a surgical procedure in an office setting. Dermatol Surg 27(7):641–644

    CAS  PubMed  Google Scholar 

  • Hasegawa M, Sato S (2008) The roles of chemokines in leukocyte recruitment and fibrosis in systemic sclerosis. Front Biosci 13:3637–3647

    CAS  PubMed  Google Scholar 

  • Honardoust D, Varkey M, Hori K, Ding J, Shankowsky HA, Tredget EE (2011) Small leucine-rich proteoglycans, decorin and fibromodulin, are reduced in postburn hypertrophic scar. Wound Repair Regen 19(3):368–378. doi:10.1111/j.1524-475X.2011.00677.x, Epub 2011 Apr 21

    PubMed  Google Scholar 

  • Honardoust D, Ding J, Varkey M, Shankowsky HA, Tredget EE (2012a) Deep Dermal Fibroblasts Refractory to Migration and Decorin-Induced Apoptosis Contribute to Hypertrophic Scarring. J Burn Care Res 2. [Epub ahead of print]

  • Honardoust D, Varkey M, Marcoux Y, Shankowsky HA, Tredget EE (2012b) Reduced decorin, fibromodulin, and transforming growth factor-β3 in deep dermis leads to hypertrophic scarring. J Burn Care Res 33(2):218–227

    PubMed  Google Scholar 

  • Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM (2007) Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma. J Biol Chem 282(31):22910–22920, Epub 2007 Jun 7

    CAS  PubMed  Google Scholar 

  • Hori K, Ding J, Marcoux Y, Iwashina T, Sakurai H, Tredget EE (2012) Impaired cutaneous wound healing in transforming growth factor-β inducible early gene1 knockout mice. Wound Repair Regen 20(2):166–177. doi:10.1111/j.1524-475X.2012.00773.x

    PubMed  Google Scholar 

  • Kilani RT, Delehanty M, Shankowsky HA, Ghahary A, Scott P, Tredget EE (2005) Fluorescent-activated cell-sorting analysis of intracellular interferon-gamma and interleukin-4 in fresh and frozen human peripheral blood T-helper cells. Wound Repair Regen 13(4):441–449

    PubMed  Google Scholar 

  • Kim BC, Kim HT, Park SH, Cha JS, Yufit T, Kim SJ, Falanga V (2003) Fibroblasts from chronic wounds show altered TGF-beta-signaling and decreased TGF-beta Type II receptor expression. J Cell Physiol 195(3):331–336

    CAS  PubMed  Google Scholar 

  • Klass BR, Grobbelaar AO, Rolfe KJ (2009) Transforming growth factor beta1 signalling, wound healing and repair: a multifunctional cytokine with clinical implications for wound repair, a delicate balance. Postgrad Med J 85(999):9–14

    CAS  PubMed  Google Scholar 

  • Kolb M, Margetts PJ, Galt T, Sime PJ, Xing Z, Schmidt M, Gauldie J (2001) Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med 163(3 Pt 1):770–777

    CAS  PubMed  Google Scholar 

  • Kopp J, Preis E, Said H, Hafemann B, Wickert L, Gressner AM, Pallua N, Dooley S (2005) Abrogation of transforming growth factor-beta signaling by SMAD7 inhibits collagen gel contraction of human dermal fibroblasts. J Biol Chem 280(22):21570–21576

    CAS  PubMed  Google Scholar 

  • Kwan P, Hori K, Ding J, Tredget EE (2009) Scar and contracture: biological principles. Hand Clin 25(4):511–528

    PubMed  Google Scholar 

  • Ladak A, Tredget EE (2009) Pathophysiology and management of the burn scar. Clin Plast Surg 36(4):661–674

    PubMed  Google Scholar 

  • Lam E, Tredget EE, Marcoux Y, Li Y, Ghahary A (2004) Insulin suppresses collagenase stimulatory effect of stratifin in dermal fibroblasts. Mol Cell Biochem 266(1–2):167–174

    CAS  PubMed  Google Scholar 

  • Lam E, Kilani RT, Li Y, Tredget EE, Ghahary A (2005) Stratifin-induced matrix metalloproteinase-1 in fibroblast is mediated by c-fos and p38 mitogen-activated protein kinase activation. J Invest Dermatol 125(2):230–238

    CAS  PubMed  Google Scholar 

  • Lee KK, Mehrany K, Swanson NA (2005) Surgical revision. Dermatol Clin 23(1):141–150, vii

    PubMed  Google Scholar 

  • Lee EK, Lee YS, Han IO, Park SH (2007) Expression of Caveolin-1 reduces cellular responses to TGF-beta1 through down-regulating the expression of TGF-beta type II receptor gene in NIH3T3 fibroblast cells. Biochem Biophys Res Commun 27;359(2):385–90. Epub 2007 May 25

    Google Scholar 

  • Liao WT, Yu HS, Arbiser JL, Hong CH, Govindarajan B, Chai CY, Shan WJ, Lin YF, Chen GS, Lee CH (2010) Enhanced MCP-1 release by keloid CD14+ cells augments fibroblast proliferation: role of MCP-1 and Akt pathway in keloids. Exp Dermatol 19(8):e142–e150

    PubMed  Google Scholar 

  • Lichtinghagen R, Michels D, Haberkorn CI, Arndt B, Bahr M, Flemming P, Manns MP, Boeker KH (2001) Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C. J Hepatol 34(2):239–247

    CAS  PubMed  Google Scholar 

  • Liu W, Chua C, Wu X, Wang D, Ying D, Cui L, Cao Y (2005) Inhibiting scar formation in rat wounds by adenovirus-mediated overexpression of truncated TGF-beta receptor II. Plast Reconstr Surg 115(3):860–870

    CAS  PubMed  Google Scholar 

  • Lu L, Saulis AS, Liu WR, Roy NK, Chao JD, Ledbetter S, Mustoe TA (2005) The temporal effects of anti-TGF-beta1, 2, and 3 monoclonal antibody on wound healing and hypertrophic scar formation. J Am Coll Surg 201(3):391–397

    PubMed  Google Scholar 

  • Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, Roers A, Eming SA (2010) Differential roles of macrophages in diverse phases of skin repair. J Immunol 1;184(7):3964–77. doi: 10.4049/jimmunol.0903356. Epub 2010 Feb 22

    Google Scholar 

  • Macintyre L, Baird M (2006) Pressure garments for use in the treatment of hypertrophic scars–a review of the problems associated with their use. Burns 32(1):10–15

    PubMed  Google Scholar 

  • Manuel JA, Gawronska-Kozak B (2006) Matrix metalloproteinase 9 (MMP-9) is upregulated during scarless wound healing in athymic nude mice. Matrix Biol 25(8):505–514, Epub 2006 Aug 16

    CAS  PubMed  Google Scholar 

  • Massagué J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791

    PubMed  Google Scholar 

  • McDougall S, Dallon J, Sherratt J, Maini P (2006) Fibroblast migration and collagen deposition during dermal wound healing: mathematical modelling and clinical implications. Philos Transact A Math Phys Eng Sci 15;364(1843):1385–1405

    Google Scholar 

  • McGee GS, Broadley KN, Buckley A, Aquino A, Woodward SC, Demetriou AA, Davidson JM (1989) Recombinant transforming growth factor beta accelerates incisional wound healing. Curr Surg 46(2):103–106

    CAS  PubMed  Google Scholar 

  • Metz CN (2003) Fibrocytes: a unique cell population implicated in wound healing. Cell Mol Life Sci 60(7):1342–1350

    CAS  PubMed  Google Scholar 

  • Miller MC, Nanchahal J (2005) Advances in the modulation of cutaneous wound healing and scarring. BioDrugs 19(6):363–381

    CAS  PubMed  Google Scholar 

  • Mirshahi F, Pourtau J, Li H, Muraine M, Trochon V, Legrand E, Vannier J, Soria J, Vasse M, Soria C (2000) SDF-1 activity on microvascular endothelial cells: consequences on angiogenesis in in vitro and in vivo models. Thromb Res 15;99(6):587–594

    Google Scholar 

  • Momeni M, Hafezi F, Rahbar H, Karimi H (2009) Effects of silicone gel on burn scars. Burns 35(1):70–74, Epub 2008 Jul 30

    PubMed  Google Scholar 

  • Monstrey S, Hoeksema H, Verbelen J, Pirayesh A, Blondeel P (2008) Assessment of burn depth and burn wound healing potential. Burns 34(6):761–769, Epub 2008 Jun 3

    PubMed  Google Scholar 

  • Monteleone G, Pallone F, MacDonald TT (2004) Smad7 in TGF-beta-mediated negative regulation of gut inflammation. Trends Immunol 25(10):513–517

    CAS  PubMed  Google Scholar 

  • Mori L, Bellini A, Stacey MA, Schmidt M, Mattoli S (2005) Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res 304(1):81–90, Epub 2004 Dec 8

    CAS  PubMed  Google Scholar 

  • Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173

    CAS  PubMed  Google Scholar 

  • Moulin V, Larochelle S, Langlois C, Thibault I, Lopez-Vallé CA, Roy M (2004) Normal skin wound and hypertrophic scar myofibroblasts have differential responses to apoptotic inductors. J Cell Physiol 198(3):350–358

    CAS  PubMed  Google Scholar 

  • Moustakas A, Heldin CH (2005) Non-Smad TGF-beta signals. J Cell Sci 118(Pt 16):3573–3584

    CAS  PubMed  Google Scholar 

  • Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X, Gulati M, Homer RJ, Russell T, van Rooijen N, Elias JA, Hogaboam CM, Herzog EL (2011) TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol 43(1):154–162. doi:10.1016/j.biocel.2010.10.013, Epub 2010 Oct 29

    CAS  PubMed  Google Scholar 

  • Mustoe TA, Cooter RD, Gold MH, Hobbs FD, Ramelet AA, Shakespeare PG, Stella M, Téot L, Wood FM, Ziegler UE (2002) International Advisory Panel on Scar Management. International clinical recommendations on scar management. Plast Reconstr Surg 110(2):560–571

    PubMed  Google Scholar 

  • Nagasawa T (2001) Role of chemokine SDF-1/PBSF and its receptor CXCR4 in blood vessel development. Ann N Y Acad Sci 947:112–115, discussion 115–6

    CAS  PubMed  Google Scholar 

  • Nedelec B, Shen YJ, Ghahary A, Scott PG, Tredget EE (1995) The effect of interferon alpha 2b on the expression of cytoskeletal proteins in an in vitro model of wound contraction. J Lab Clin Med 126(5):474–484

    CAS  PubMed  Google Scholar 

  • Nedelec B, Ghahary A, Scott PG, Tredget EE (2000) Control of wound contraction. Basic and clinical features. Hand Clin 16(2):289–302

    CAS  PubMed  Google Scholar 

  • Nedelec B, Shankowsky H, Scott PG, Ghahary A, Tredget EE (2001) Myofibroblasts and apoptosis in human hypertrophic scars: the effect of interferon-alpha2b. Surgery 130(5):798–808

    CAS  PubMed  Google Scholar 

  • O’Sullivan ST, Lederer JA, Horgan AF, Chin DH, Mannick JA, Rodrick ML (1995) Major injury leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin-12 production associated with decreased resistance to infection. Ann Surg 222(4):482–490, discussion 490–2

    PubMed Central  PubMed  Google Scholar 

  • Pannu J, Nakerakanti S, Smith E, ten Dijke P, Trojanowska M (2007) Transforming growth factor-beta receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways. J Biol Chem 282(14):10405–10413

    CAS  PubMed  Google Scholar 

  • Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R (2004) Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol 36(4):598–606

    CAS  PubMed  Google Scholar 

  • Reinke JM, Sorg H (2012) Wound Repair and Regeneration. Eur Surg Res 11;49(1):35–43

    Google Scholar 

  • Reynolds JJ (1996) Collagenases and tissue inhibitors of metalloproteinases: a functional balance in tissue degradation. Oral Dis 2(1):70–76

    CAS  PubMed  Google Scholar 

  • Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH et al (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 U S A 83(12):4167–4171

    CAS  PubMed Central  PubMed  Google Scholar 

  • Saito S, Trovato MJ, You R, Lal BK, Fasehun F, Padberg FT Jr, Hobson RW 2nd, Durán WN, Pappas PJ (2001) Role of matrix metalloproteinases 1, 2, and 9 and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufficiency. J Vasc Surg 34(5):930–938

    CAS  PubMed  Google Scholar 

  • Sarkhosh K, Tredget EE, Karami A, Uludag H, Iwashina T, Kilani RT, Ghahary A (2003) Immune cell proliferation is suppressed by the interferon-gamma-induced indoleamine 2,3-dioxygenase expression of fibroblasts populated in collagen gel (FPCG). J Cell Biochem 90(1):206–217

    CAS  PubMed  Google Scholar 

  • Sawicki G, Marcoux Y, Sarkhosh K, Tredget EE, Ghahary A (2005) Interaction of keratinocytes and fibroblasts modulates the expression of matrix metalloproteinases-2 and −9 and their inhibitors. Mol Cell Biochem 269(1–2):209–216

    CAS  PubMed  Google Scholar 

  • Sayani K, Dodd CM, Nedelec B, Shen YJ, Ghahary A, Tredget EE, Scott PG (2000) Delayed appearance of decorin in healing burn scars. Histopathology 36(3):262–272

    CAS  PubMed  Google Scholar 

  • Schönherr E, Hausser HJ (2000) Extracellular matrix and cytokines: a functional unit. Dev Immunol 7(2–4):89–101

    PubMed Central  PubMed  Google Scholar 

  • Scott PG, Dodd CM, Tredget EE, Ghahary A, Rahemtulla F (1995) Immunohistochemical localization of the proteoglycans decorin, biglycan and versican and transforming growth factor-beta in human post-burn hypertrophic and mature scars. Histopathology 26(5):423–431

    CAS  PubMed  Google Scholar 

  • Scott PG, Ghahary A, Tredget EE (2000) Molecular and cellular aspects of fibrosis following thermal injury. Hand Clin 16(2):271–287

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Shah M, Foreman DM, Ferguson MW (1995) Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci 108(Pt 3):985–1002

    CAS  PubMed  Google Scholar 

  • Shi-wen X, Stanton LA, Kennedy L, Pala D, Chen Y, Howat SL, Renzoni EA, Carter DE, Bou-Gharios G, Stratton RJ, Pearson JD, Beier F, Lyons KM, Black CM, Abraham DJ, Leask A (2006) CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts. J Biol Chem 21;281(16):10715–10726. Epub 2006 Feb 16

    Google Scholar 

  • Sidgwick GP, Bayat A (2012) Extracellular matrix molecules implicated in hypertrophic and keloid scarring. J Eur Acad Dermatol Venereol 26(2):141–152

    CAS  PubMed  Google Scholar 

  • Simon F, Bergeron D, Larochelle S, Lopez-Vallé CA, Genest H, Armour A, Moulin VJ (2012) Enhanced secretion of TIMP-1 by human hypertrophic scar keratinocytes could contribute to fibrosis. Burns 38(3):421–427, Epub 2011 Oct 29

    PubMed  Google Scholar 

  • Sorrell JM, Caplan AI (2004) Fibroblast heterogeneity: more than skin deep. J Cell Sci 117(Pt 5):667–675

    CAS  PubMed  Google Scholar 

  • Stamenkovic I (2003) Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol 200(4):448–464

    CAS  PubMed  Google Scholar 

  • Stopa M, Anhuf D, Terstegen L, Gatsios P, Gressner AM, Dooley S (2000) Participation of Smad2, Smad3, and Smad4 in transforming growth factor beta (TGF-beta)-induced activation of Smad7. THE TGF-beta response element of the promoter requires functional Smad binding element and E-box sequences for transcriptional regulation. J Biol Chem 275(38):29308–29317

    CAS  PubMed  Google Scholar 

  • Tanriverdi-Akhisaroglu S, Menderes A, Oktay G (2009) Matrix metalloproteinase-2 and −9 activities in human keloids, hypertrophic and atrophic scars: a pilot study. Cell Biochem Funct 27(2):81–87

    CAS  PubMed  Google Scholar 

  • Tredget EE (1999) Pathophysiology and treatment of fibroproliferative disorders following thermal injury. Ann N Y Acad Sci 888:165–182

    CAS  PubMed  Google Scholar 

  • Tredget EE, Nedelec B, Scott PG, Ghahary A (1997) Hypertrophic scars, keloids, and contractures. The cellular and molecular basis for therapy. Surg Clin North Am 77(3):701–730

    CAS  PubMed  Google Scholar 

  • Tredget EE, Shankowsky HA, Pannu R, Nedelec B, Iwashina T, Ghahary A, Taerum TV, Scott PG (1998) Transforming growth factor-beta in thermally injured patients with hypertrophic scars: effects of interferon alpha-2b. Plast Reconstr Surg 102(5):1317–1328, discussion 1329–30

    CAS  PubMed  Google Scholar 

  • Tredget EE, Wang R, Shen Q, Scott PG, Ghahary A (2000) Transforming growth factor-beta mRNA and protein in hypertrophic scar tissues and fibroblasts: antagonism by IFN-alpha and IFN-gamma in vitro and in vivo. J Interferon Cytokine Res 20(2):143–151

    CAS  PubMed  Google Scholar 

  • Tredget EE, Yang L, Delehanty M, Shankowsky H, Scott PG (2006) Polarized Th2 cytokine production in patients with hypertrophic scar following thermal injury. J Interferon Cytokine Res 26(3):179–189

    CAS  PubMed  Google Scholar 

  • Ulrich D, Noah EM, von Heimburg D, Pallua N (2003) TIMP-1, MMP-2, MMP-9, and PIIINP as serum markers for skin fibrosis in patients following severe burn trauma. Plast Reconstr Surg 1;111(4):1423–1431

    Google Scholar 

  • Vaalamo M, Leivo T, Saarialho-Kere U (1999) Differential expression of tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and −4) in normal and aberrant wound healing. Hum Pathol 30(7):795–802

    CAS  PubMed  Google Scholar 

  • Wang R, Ghahary A, Shen YJ, Scott PG, Tredget EE (1996) Human dermal fibroblasts produce nitric oxide and express both constitutive and inducible nitric oxide synthase isoforms. J Invest Dermatol 106(3):419–427

    CAS  PubMed  Google Scholar 

  • Wang R, Ghahary A, Shen Q, Scott PG, Roy K, Tredget EE (2000) Hypertrophic scar tissues and fibroblasts produce more transforming growth factor-beta1 mRNA and protein than normal skin and cells. Wound Repair Regen 8(2):128–137

    CAS  PubMed  Google Scholar 

  • Wang B, Hao J, Jones SC, Yee MS, Roth JC, Dixon IM (2002) Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am J Physiol Heart Circ Physiol 282(5):H1685–H1696

    CAS  PubMed  Google Scholar 

  • Wang J, Jiao H, Stewart TL, Lyons MV, Shankowsky HA, Scott PG, Tredget EE (2007a) Accelerated wound healing in leukocyte-specific, protein 1-deficient mouse is associated with increased infiltration of leukocytes and fibrocytes. J Leukoc Biol 82(6):1554–1563

    CAS  PubMed  Google Scholar 

  • Wang JF, Jiao H, Stewart TL, Shankowsky HA, Scott PG, Tredget EE (2007b) Fibrocytes from burn patients regulate the activities of fibroblasts. Wound Repair Regen 15(1):113–121

    PubMed  Google Scholar 

  • Wang J, Jiao H, Stewart TL, Shankowsky HA, Scott PG, Tredget EE (2007c) Increased TGF-beta-producing CD4+ T lymphocytes in postburn patients and their potential interaction with dermal fibroblasts in hypertrophic scarring. Wound Repair Regen 15(4):530–539

    PubMed  Google Scholar 

  • Wang J, Chen H, Shankowsky HA, Scott PG, Tredget EE (2008a) Improved scar in postburn patients following interferon-alpha2b treatment is associated with decreased angiogenesis mediated by vascular endothelial cell growth factor. J Interferon Cytokine Res 28(7):423–434

    CAS  PubMed  Google Scholar 

  • Wang J, Dodd C, Shankowsky HA, Scott PG, Tredget EE, Wound Healing Research Group (2008b) Deep dermal fibroblasts contribute to hypertrophic scarring. Lab Invest 88(12):1278–1290, Epub 2008 Oct 27

    CAS  PubMed  Google Scholar 

  • Wang J, Ding J, Jiao H, Honardoust D, Momtazi M, Shankowsky HA, Tredget EE (2011a) Human hypertrophic scar-like nude mouse model: characterization of the molecular and cellular biology of the scar process. Wound Repair Regen 19(2):274–285

    PubMed  Google Scholar 

  • Wang J, Hori K, Ding J, Huang Y, Kwan P, Ladak A, Tredget EE (2011b) Toll-like receptors expressed by dermal fibroblasts contribute to hypertrophic scarring. J Cell Physiol 226(5):1265–1273. doi:10.1002/jcp.22454

    CAS  PubMed  Google Scholar 

  • Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83(3):835–870

    CAS  PubMed  Google Scholar 

  • Wynn TA (2004) Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 4(8):583–594

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xie JL, Bian HN, Qi SH, Chen HD, Li HD, Xu YB, Li TZ, Liu XS, Liang HZ, Xin BR, Huan Y (2008) Basic fibroblast growth factor (bFGF) alleviates the scar of the rabbit ear model in wound healing. Wound Repair Regen 16(4):576–581

    PubMed  Google Scholar 

  • Xu LL, Warren MK, Rose WL, Gong W, Wang JM (1996) Human recombinant monocyte chemotactic protein and other C-C chemokines bind and induce directional migration of dendritic cells in vitro. J Leukoc Biol 60(3):365–371

    CAS  PubMed  Google Scholar 

  • Xu SW, Howat SL, Renzoni EA, Holmes A, Pearson JD, Dashwood MR, Bou-Gharios G, Denton CP, du Bois RM, Black CM, Leask A, Abraham DJ (2004) Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem 28;279(22):23098–23103

    Google Scholar 

  • Xu J, Mora A, Shim H, Stecenko A, Brigham KL, Rojas M (2007) Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis. Am J Respir Cell Mol Biol 37(3):291–299, Epub 2007 Apr 26

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang L, Tredget EE, Ghahary A (2000) Activation of latent transforming growth factor-beta1 is induced by mannose 6-phosphate/insulin-like growth factor-II receptor. Wound Repair Regen 8(6):538–546

    CAS  PubMed  Google Scholar 

  • Yang L, Chan T, Demare J, Iwashina T, Ghahary A, Scott PG, Tredget EE (2001) Healing of burn wounds in transgenic mice overexpressing transforming growth factor-beta 1 in the epidermis. Am J Pathol 159(6):2147–2157

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang L, Scott PG, Giuffre J, Shankowsky HA, Ghahary A, Tredget EE (2002) Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells. Lab Invest 82(9):1183–1192

    CAS  PubMed  Google Scholar 

  • Yang L, Scott PG, Dodd C, Medina A, Jiao H, Shankowsky HA, Ghahary A, Tredget EE (2005) Identification of fibrocytes in postburn hypertrophic scar. Wound Repair Regen 13(4):398–404

    PubMed  Google Scholar 

  • Yuan W, Varga J (2001) Transforming growth factor-beta repression of matrix metalloproteinase-1 in dermal fibroblasts involves Smad3. J Biol Chem 19;276(42):38502–38510. Epub 2001 Aug 13

    Google Scholar 

  • Zhang GY, He B, Liao T, Luan Q, Tao C, Nie CL, Albers AE, Zheng X, Xie XG, Gao WY (2011a) Caveolin 1 inhibits transforming growth factor-β1 activity via inhibition of Smad signaling by hypertrophic scar derived fibroblasts in vitro. J Dermatol Sci 62(2):128–131, Epub 2011 Feb 24

    CAS  PubMed  Google Scholar 

  • Zhang ZF, Zhang YG, Hu DH, Shi JH, Liu JQ, Zhao ZT, Wang HT, Bai XZ, Cai WX, Zhu HY, Tang CW (2011b) Smad interacting protein 1 as a regulator of skin fibrosis in pathological scars. Burns 37(4):665–672, Epub 2011 Jan 14

    PubMed  Google Scholar 

  • Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393(6685):595–599

    CAS  PubMed  Google Scholar 

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Correspondence to Edward E. Tredget.

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This work was supported by the Canadian Institutes of Health Research and the Firefighters’ Burn Trust Fund of the University of Alberta.

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Zhu, Z., Ding, J., Shankowsky, H.A. et al. The molecular mechanism of hypertrophic scar. J. Cell Commun. Signal. 7, 239–252 (2013). https://doi.org/10.1007/s12079-013-0195-5

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