Current and Upcoming Therapies to Modulate Skin Scarring and Fibrosis
Total Page：16
File Type：pdf, Size：1020Kb
Advanced Drug Delivery Reviews 146 (2019) 37–59 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Current and upcoming therapies to modulate skin scarring and fibrosis João Q. Coentro a ,b ,1 , Eugenia Pugliese a ,b ,1 , Geoffrey Hanley a ,b , Michael Raghunath c , Dimitrios I. Zeugolis a ,b ,⁎ a Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI, Galway), Galway, Ireland b Science Foundation Ireland (SFI), Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI, Galway), Galway, Ireland c Center for Cell Biology and Tissue Engineering, Institute for Chemistry and Biotechnology (ICBT), Zurich University of Applied Sciences (ZHAW), Wädenswil, Switzerland article info abstract Article history: Skin is the largest organ of the human body. Being the interface between the body and the outer environment, Received 7 April 2018 makes it susceptible to physical injury. To maintain life, nature has endowed skin with a fast healing response Received in revised form 8 July 2018 that invariably ends in the formation of scar at the wounded dermal area. In many cases, skin remodelling may Accepted 26 August 2018 be impaired, leading to local hypertrophic scars or keloids. One should also consider that the scarring process Available online 30 August 2018 is part of the wound healing response, which always starts with inflammation. Thus, scarring can also be induced in the dermis, in the absence of an actual wound, during chronic inflammatory processes. Considering the signif- Keywords: Hypertrophic scars icant portion of the population that is subject to abnormal scarring, this review critically discusses the state-of- Keloid the-art and upcoming therapies in skin scarring and fibrosis. Scleroderma © 2018 Elsevier B.V. All rights reserved. Systemic sclerosis Myofibroblasts Scarring Collagen synthesis Collagen deposition Inflammation Wound healing Remodelling Contents 1. Introduction............................................................... 38 2. Methodsofdiagnosisandbiomarkerassessment............................................... 40 3. Modulation of the inflammationphase................................................... 40 3.1. Targeting inflammatorycells.................................................... 41 3.2. Targeting the mediators of the inflammationresponse......................................... 42 4. Modulationoftheproliferativephase.................................................... 42 4.1. Inhibitors of post-translational modifiersofcollagen.......................................... 44 4.1.1. Prolylhydroxylaseinhibitors................................................ 44 4.1.2. Lysinehydroxylaseinhibitors................................................ 44 4.1.3. Inhibitorsofprocollagenconversion............................................. 45 4.1.4. Inhibitorsofcollagencross-linking............................................. 45 4.2. Modulation of myofibroblastactivation................................................ 45 Abbreviations: 5-FU, 5-Fluroruracil; α-SMA, α- Smooth Muscle Actin; AKT, Protein Kinase B; BLM, Bleomycin; BMP-1, Bone Morphogenetic Protein 1; CTGF/CCN2, Connective Tissue Growth Factor; ECM, Extracellular Matrix; EGFR, Epidermal Growth Factor Receptor; GF, Growth Factor; HA, Hyaluronic Acid; HGF, Hepatocyte Growth Factor; IGF-1, Insulin-like Growth Factor 1; IFN, Interferon; IL, Interleukin; KF, Keloid-derived Fibroblasts; LOX, Lysyl Oxidase; M6P, Mannose-6-Phosphate; MMP, Matrix Metalloproteinase; miRNA, Micro RNA; mRNA, Messenger RNA; mTOR, Mammalian Target of Rapamycin; NOX-4, NADPH-Oxidase 4; PAI1, Plasminogen Activator Inhibitor 1; PDGF, Platelet-Derived Growth Factor; PHI, Prolyl Hydroxylase Inhibitor; PI3K, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase; PPAR, Peroxisome Proliferator-Activated Receptors; ROS, Reactive Oxygen Species; SiRNA, Small Interfering RNA/Silencing RNA; SMAD, Small Mothers Against Decapentaplegic; SSc, Systemic Sclerosis; TAC, Triamcinolone Acetonide; TGF-β, Transforming Growth Factor β;Th,Thelper; T-killer, Cytotoxic T cell; TLR, Toll Like Receptor; TNF-α, Tumour Necrosis Factor α; Treg, Regulatory T cells; Trm, Resident Memory T cells. ⁎ Corresponding author. E-mail address: [email protected] (D.I. Zeugolis). 1 JQC and EP share first authorship. https://doi.org/10.1016/j.addr.2018.08.009 0169-409X/© 2018 Elsevier B.V. All rights reserved. 38 J.Q. Coentro et al. / Advanced Drug Delivery Reviews 146 (2019) 37–59 4.3. Interfering with fibrogenicgrowthfactors...............................................47 5. Post-scarringtherapiestoemulateremodelling...............................................48 5.1. Transdermalinjections.......................................................49 5.2. Biomaterial-basedapproaches....................................................49 5.3. Non-pharmacologicalapproaches..................................................51 6. Conclusionsandfutureperspectives.....................................................52 Competing financialinterests..........................................................52 Acknowledgements..............................................................52 References...................................................................52 1. Introduction immune system to the wound area (monocytes, neutrophil granulocytes), fighting local infection and phagocytosing local debris Scar formation is the end result of the repair process after a tissue and damaged connective tissue, and also subsequently removing fibrin. has been wounded. There is one exception to this feature in humans: The cells involved here produce inflammatory cytokines, such as the human foetus heals without, or almost without, scar formation in transforming growth factor β (TGF-β)[5], interleukin 4 and 13 (IL-4 the first three months of a pregnancy [1]. Depending on the wounding and IL-13) [6] and tumour necrosis factor α (TNF-α)[7]. This ushers in mechanism, the scarring wound healing response has a pathological the proliferative phase, whereby fibroblasts enter the scene and begin spectrum, ranging from cosmetic annoyance to grave functional impair- to build up fresh connective tissue. For this to occur, these fibroblasts ment (i.e. scar traction across joints, impeding facial muscular move- display an activated phenotype, the myofibroblast. Myofibroblasts are ment). The classical wound healing stages in the skin that lead to specialised contractile cells characterised by expression of α-smooth scarring are well characterised [2–4]. It is however important to under- muscle actin (α-SMA) [8], a splice variant of fibronectin [9], an amine stand the stages of wound healing to identify key points for therapeutic oxidase copper containing 3 protein [10] and a fibroblast activation pro- intervention and to derive and employ efficacious pharmacological tein [11] and produce and deposit large amounts of collagen. compounds (Fig. 1). Thus, herein we briefly recount these phases. Myofibroblast origin can be traced back to different cells and it is still With the initial traumatic event comes bleeding and the initiation of co- not completely understood. The major contribution comes from the in agulation cascade resulting in a blood clot (later, scab). Platelets are situ activation of resident fibroblasts in response to different triggers, trapped within the blood clot and, in contact with exposed collagen, such as TGF-β1, Jagged/Notch, Connective Tissue Growth Factor/CCN they bind to it and get activated, thus releasing multiple factors. As de- Family Member 2 (CTGF/CCN2), endothelin-1, lysophosphatidic acid, fined here, this represents stage zero of wound healing. The next stage, and other signalling molecules, as well as hypoxia and mechanical stress the inflammatory phase, sees the recruitment of cells of the innate due to increased extracellular matrix (ECM) stiffness [12]. Fig. 1. Pathological scarring cycle and associated therapeutic targets. Scarring phenomena share three common phases after wounding: chronic inflammation, proliferative and remodelling phase. In this review, the different therapeutic approaches that can be pursued in each phase will be highlighted, by discussing their advantages and limitations, for a better understanding of the therapeutic potential for the treatment of skin fibrosis. J.Q. Coentro et al. / Advanced Drug Delivery Reviews 146 (2019) 37–59 39 Mesenchymal stem cells [13] and circulating cells, called fibrocytes, [14] note, a tissue area undergoing fibrotic change might be a cradle for have also been proposed as actors in the tissue repair process. Alterna- epithelial-mesenchymal or mesenchymal-epithelial transformation, tively, myofibroblasts may arise from other cell types, including epithe- preparing the ground for cancer formation. [27,28]. lial cells in the skin or lungs vascular smooth muscle cells and pericytes Despite its enormous impact on human health, there has been no [12]. The cells partially break down collagen fibres and splice de novo real breakthrough in fibrosis therapy. This may be due to the logic of collagen fibres with those bordering the tissue interruption. The fibro- antifibrotic treatment in general. Scar formation and fibrosis can be pre- blasts are specialised to make connective tissue, and in the skin, the dicted in the case of implanting (often drug delivering) biomaterials or major component