Cytokines, chemokines and growth factors in wound healing

In wound healing, a variety of mediators have been identified throughout the years. The mediators discussed here comprise growth factors, cytokines and chemokines. These mediators act via multiple (specific) receptors to facilitate wound closure. As research in the last years has led to many new findings, there is a need to give an overview on what is known, and on what might possibly play a role as a molecular target for future wound therapy. This review aims to keep the reader up to date with selected important and novel findings regarding growth factors, cytokines and chemokines in wound healing.

[1]  Leaf Huang,et al.  Intradermal Injection of Transforming Growth Factor-β1 Gene Enhances Wound Healing in Genetically Diabetic Mice , 2003, Pharmaceutical Research.

[2]  Richard O. Hynes,et al.  The Extracellular Matrix: Not Just Pretty Fibrils , 2009, Science.

[3]  K. Forsman-Semb,et al.  Mice with Targeted Mutation of Peroxiredoxin 6 Develop Normally but Are Susceptible to Oxidative Stress* , 2003, Journal of Biological Chemistry.

[4]  M. Fujimoto,et al.  Endothelial selectins regulate skin wound healing in cooperation with L‐selectin and ICAM‐1 , 2007, Journal of leukocyte biology.

[5]  S. Kozma,et al.  Differences in Wound Healing in Mice with Deficiency of IL-6 versus IL-6 Receptor , 2010, The Journal of Immunology.

[6]  K. Yoshikawa,et al.  Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation. , 2003, The Journal of investigative dermatology.

[7]  Tarynn M Witten,et al.  Impaired wound healing. , 2007, Clinics in dermatology.

[8]  P. Elias,et al.  Barrier disruption stimulates interleukin-1 alpha expression and release from a pre-formed pool in murine epidermis. , 1996, The Journal of investigative dermatology.

[9]  O. Stojadinović,et al.  Attenuation of the Transforming Growth Factor β-Signaling Pathway in Chronic Venous Ulcers , 2010, Molecular medicine.

[10]  B. Cronstein,et al.  Wound healing is impaired in MyD88-deficient mice: a role for MyD88 in the regulation of wound healing by adenosine A2A receptors. , 2007, The American journal of pathology.

[11]  Matthias Schäfer,et al.  Oxidative stress in normal and impaired wound repair. , 2008, Pharmacological research.

[12]  J. Davidson.  First-class delivery: getting growth factors to their destination. , 2008, The Journal of investigative dermatology.

[13]  G F Pierce,et al.  Platelet-derived growth factor (BB homodimer), transforming growth factor-beta 1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair. , 1992, The American journal of pathology.

[14]  A. Wells,et al.  Glu-Leu-Arg-negative CXC chemokine interferon gamma inducible protein-9 as a mediator of epidermal-dermal communication during wound repair. , 2003, The Journal of investigative dermatology.

[15]  Jerry S. Vandeberg,et al.  Sequential cytokine therapy for pressure ulcers: clinical and mechanistic response. , 2000, Annals of surgery.

[16]  M. Landthaler,et al.  Oxygen in acute and chronic wound healing , 2010, The British journal of dermatology.

[17]  A. Roberts,et al.  Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-alpha and TGF-beta. , 2005, Journal of cell science.

[18]  W. Wahli,et al.  Critical roles of the nuclear receptor PPARbeta (peroxisome-proliferator-activated receptor beta) in skin wound healing. , 2004, Biochemical Society transactions.

[19]  Takayuki Asahara,et al.  The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors , 2001, Nature Medicine.

[20]  K. Matsushima,et al.  Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-kappaB activation and a reciprocal suppression of TGF-beta signal pathway. , 2006, Journal of immunology.

[21]  S. Sato,et al.  Delayed wound healing in the absence of intercellular adhesion molecule-1 or L-selectin expression. , 2000, The American journal of pathology.

[22]  P. Murphy,et al.  Chemokine Receptor CX3CR1 Mediates Skin Wound Healing by Promoting Macrophage and Fibroblast Accumulation and Function1 , 2008, The Journal of Immunology.

[23]  S. Warren,et al.  Hedgehog signaling is essential for normal wound healing , 2008, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[24]  Jun Asai,et al.  Topical Sonic Hedgehog Gene Therapy Accelerates Wound Healing in Diabetes by Enhancing Endothelial Progenitor Cell–Mediated Microvascular Remodeling , 2006, Circulation.

[25]  A. Grobbelaar,et al.  Transforming growth factor β1 signalling, wound healing and repair: a multifunctional cytokine with clinical implications for wound repair, a delicate balance , 2009, Postgraduate Medical Journal.

[26]  G. Marti,et al.  KGF-1 for wound healing in animal models. , 2008, Methods in molecular biology.

[27]  S. Werner,et al.  Fibroblast growth factors in epithelial repair and cytoprotection. , 2004, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[28]  A. Roberts,et al.  Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-α and TGF-β , 2005, Journal of Cell Science.

[29]  Anita B. Roberts,et al.  Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response , 1999, Nature Cell Biology.

[30]  Timothy A. Dall,et al.  The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. , 2006, Journal of the American Academy of Dermatology.

[31]  Tadeusz Malinski,et al.  Role of nitric oxide, nitroxidative and oxidative stress in wound healing. , 2005, Pharmacological reports : PR.

[32]  E. Mekada,et al.  Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing , 2005, Journal of Cell Science.

[33]  L. Lau,et al.  The Angiogenic Factor Cyr61 Activates a Genetic Program for Wound Healing in Human Skin Fibroblasts* , 2001, The Journal of Biological Chemistry.

[34]  C. Green,et al.  Targeting Connexin43 Expression Accelerates the Rate of Wound Repair , 2003, Current Biology.

[35]  K. Matsushima,et al.  Absence of IL-1 Receptor Antagonist Impaired Wound Healing along with Aberrant NF-κB Activation and a Reciprocal Suppression of TGF-β Signal Pathway1 , 2006, The Journal of Immunology.

[36]  P. Schirmacher,et al.  Resistance of keratinocytes to TGFbeta-mediated growth restriction and apoptosis induction accelerates re-epithelialization in skin wounds. , 2002, Journal of cell science.

[37]  M. Blumenberg,et al.  Epidermal growth factor and transforming growth factor alpha specifically induce the activation- and hyperproliferation-associated keratins 6 and 16. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Simona Storti,et al.  SERCA2a, Phospholamban, Sarcolipin, and Ryanodine Receptors Gene Expression in Children with Congenital Heart Defects , 2007, Molecular medicine.

[39]  M. Mori,et al.  Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo , 2001, FEBS letters.

[40]  O. Ishikawa,et al.  Basic fibroblast growth factor stimulates human keratinocyte motility by Rac activation , 2006, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[41]  D. Sheppard,et al.  Cross talk among TGF-β signaling pathways, integrins, and the extracellular matrix. , 2011, Cold Spring Harbor perspectives in biology.

[42]  H. Moses,et al.  Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta , 1987, Journal of Experimental Medicine.

[43]  Y. Gho,et al.  Hepatocyte Growth Factor Suppresses Vascular Endothelial Growth Factor–Induced Expression of Endothelial ICAM-1 and VCAM-1 by Inhibiting the Nuclear Factor-&kgr;B Pathway , 2005 .

[44]  M. P. Welch,et al.  TGF-beta 1 stimulates expression of keratinocyte integrins during re-epithelialization of cutaneous wounds. , 1994, The Journal of investigative dermatology.

[45]  S. Werner,et al.  Activin: an important regulator of wound repair, fibrosis, and neuroprotection , 2004, Molecular and Cellular Endocrinology.

[46]  J. Varga,et al.  Transforming Growth Factor-β Repression of Matrix Metalloproteinase-1 in Dermal Fibroblasts Involves Smad3* , 2001, The Journal of Biological Chemistry.

[47]  R. Busse,et al.  Oxidative stress and expression of p22phox are involved in the up‐regulation of tissue factor in vascular smooth muscle cells in response to activated platelets , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  P. Bugnon,et al.  Peroxiredoxin 6 is required for blood vessel integrity in wounded skin. , 2007, The Journal of cell biology.

[49]  D. Greenhalgh,et al.  PDGF and FGF stimulate wound healing in the genetically diabetic mouse. , 1990, The American journal of pathology.

[50]  S. Werner,et al.  c-Met is essential for wound healing in the skin , 2007, The Journal of cell biology.

[51]  W. Wahli,et al.  Critical roles of the nuclear receptor PPARβ (peroxisome-proliferator-activated receptor β) in skin wound healing , 2004 .

[52]  S. Ehlers,et al.  Alternatively activated macrophages express the IL-27 receptor alpha chain WSX-1. , 2006, Immunobiology.

[53]  H. Schluesener,et al.  Mammalian toll-like receptors: from endogenous ligands to tissue regeneration , 2006, Cellular and Molecular Life Sciences CMLS.

[54]  Olivera Stojadinovic,et al.  PERSPECTIVE ARTICLE: Growth factors and cytokines in wound healing , 2008, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[55]  S. Werner,et al.  Keratinocyte-derived follistatin regulates epidermal homeostasis and wound repair , 2009, Laboratory Investigation.

[56]  Olivera Stojadinovic,et al.  Molecular Markers in Patients with Chronic Wounds to Guide Surgical Debridement , 2007, Molecular medicine.

[57]  C. Wiegand,et al.  Protease and pro-inflammatory cytokine concentrations are elevated in chronic compared to acute wounds and can be modulated by collagen type I in vitro , 2010, Archives of Dermatological Research.

[58]  N. Mukaida,et al.  Essential involvement of IL‐6 in the skin wound‐healing process as evidenced by delayed wound healing in IL‐6‐deficient mice , 2003, Journal of leukocyte biology.

[59]  D. Meldrum,et al.  MEK, p38, and PI-3K mediate cross talk between EGFR and TNFR in enhancing hepatocyte growth factor production from human mesenchymal stem cells. , 2009, American journal of physiology. Cell physiology.

[60]  M. Stepp,et al.  Loss of integrin alpha9beta1 results in defects in proliferation, causing poor re-epithelialization during cutaneous wound healing. , 2009, The Journal of investigative dermatology.

[61]  M. Sporn,et al.  Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[62]  K. Hörmann,et al.  TGF-beta antisense oligonucleotides reduce mRNA expression of matrix metalloproteinases in cultured wound-healing-related cells. , 2005, International journal of molecular medicine.

[63]  Vandana Iyer,et al.  Integrin alpha3beta1 potentiates TGFbeta-mediated induction of MMP-9 in immortalized keratinocytes. , 2008, The Journal of investigative dermatology.

[64]  D. Dill,et al.  The Role of Interleukin-1 in Wound Biology. Part II: In Vivo and Human Translational Studies , 2010, Anesthesia and analgesia.

[65]  A. Gurney,et al.  IL-22 Inhibits Epidermal Differentiation and Induces Proinflammatory Gene Expression and Migration of Human Keratinocytes1 , 2005, The Journal of Immunology.

[66]  J. Arbeit,et al.  c-Jun is essential for organization of the epidermal leading edge. , 2003, Developmental cell.

[67]  P. Hofschneider,et al.  The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. , 1994, Science.

[68]  Thiennu H. Vu,et al.  Epidermal development and wound healing in matrix metalloproteinase 13-deficient mice. , 2006, The Journal of investigative dermatology.

[69]  W. Wahli,et al.  Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway. , 2002, Molecular cell.

[70]  D. Paul,et al.  Wounding alters epidermal connexin expression and gap junction-mediated intercellular communication. , 1995, Molecular biology of the cell.

[71]  S. Werner,et al.  The Mad1 transcription factor is a novel target of activin and TGF-β action in keratinocytes: possible role of Mad1 in wound repair and psoriasis , 2001, Oncogene.

[72]  A. Desmoulière,et al.  Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts , 1993, The Journal of cell biology.

[73]  R. Bodnar,et al.  Delayed and deficient dermal maturation in mice lacking the CXCR3 ELR-negative CXC chemokine receptor. , 2007, The American journal of pathology.

[74]  T. K. Hunt,et al.  Human skin wounds: A major and snowballing threat to public health and the economy , 2009, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[75]  G. Schultz,et al.  Interactions of cytokines, growth factors, and proteases in acute and chronic wounds , 1996, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[76]  D. Becker,et al.  Dynamic changes in connexin expression correlate with key events in the wound healing process , 2003, Cell biology international.

[77]  Y. Gho,et al.  Hepatocyte growth factor suppresses vascular endothelial growth factor-induced expression of endothelial ICAM-1 and VCAM-1 by inhibiting the nuclear factor-kappaB pathway. , 2005, Circulation research.

[78]  S. Werner,et al.  Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. , 1996, Cytokine.

[79]  Sabine Werner,et al.  Roles of activin in tissue repair, fibrosis, and inflammatory disease. , 2006, Cytokine & growth factor reviews.

[80]  S. Akira,et al.  Keratinocyte‐specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis , 1999, The EMBO journal.

[81]  S. Werner,et al.  Roles and mechanisms of action of the Nrf2 transcription factor in skin morphogenesis, wound repair and skin cancer , 2007, Cell Death and Differentiation.

[82]  M. Paulsson,et al.  Alternative proteolytic processing of hepatocyte growth factor during wound repair. , 2009, The American journal of pathology.

[83]  H. Kitano,et al.  A comprehensive pathway map of epidermal growth factor receptor signaling , 2005, Molecular systems biology.

[84]  Hyung Jin Kim,et al.  Vascular Endothelial Growth Factor Expression of Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), and E-selectin through Nuclear Factor-κB Activation in Endothelial Cells* , 2001, The Journal of Biological Chemistry.

[85]  D. Rifkin,et al.  Biological roles of fibroblast growth factor-2. , 1997, Endocrine reviews.

[86]  Vandana Iyer,et al.  Integrin α3β1 potentiates TGFβ-mediated induction of MMP-9 in immortalized keratinocytes , 2008 .

[87]  C. Powers,et al.  Fibroblast growth factors, their receptors and signaling. , 2000, Endocrine-related cancer.

[88]  J. Edwards,et al.  Exploring the full spectrum of macrophage activation , 2008, Nature Reviews Immunology.

[89]  J. Brandner,et al.  Connexin 43 mimetic peptide Gap27 reveals potential differences in the role of Cx43 in wound repair between diabetic and non-diabetic cells , 2010, Journal of cellular and molecular medicine.