Systematic Review on Working Mechanisms of Signaling Pathways in Fibrosis During Shockwave Therapy

Abstract

Fibrosis is characterized by scarring and hardening of tissues and organs. It can affect every organ system, and so could result in organ failure due to the accumulation of extracellular matrix proteins. Previous studies suggest that mechanical forces (such as shockwave therapy, SWT) initiate a process of mechanotransduction and thus could regulate fibrosis. Nevertheless, it is largely unexamined which pathways are exactly involved in the application of SWT and can regulate fibrosis. The present article seeks to elucidate the underlying effect of SWT on fibrosis. Evidence shows that SWT activates macrophage activity, fibroblast activity, collagen amount and orientation and apoptosis, which ultimately lead to an adaptation of inflammation, proliferation, angiogenesis and apoptosis. The included articles reveal that other proteins and pathways can be activated depending on the energy levels and frequency of SWT. These findings demonstrate that SWT has beneficial effects on fibrosis by influencing the proteins and pathways. Based on these data, which highlights the underlying mechanisms, we can make preliminary conclusions about the treatment modalities of SWT in scar formation, such as the energy levels and frequencies that are necessary to prevent or treat fibrotic tissue.

Keywords: fibrosis; shockwave therapy; underlying mechanisms.

Figure 1

PRISMA flowchart: an overview of the inclusion and exclusion process. Abbreviations: n = numbers.

Figure 2

Overview of the included tissues and specific type of fibrosis. In parentheses in the headings the number of articles per tissue (=N) and also the references. Abbreviations: OA = osteoarthritis, ACL = anterior cruciate ligament [3,4,5,6,7,8,9,10,11,12,18,19,20,23,24,25,26,27,28,29,30,31,32,33,37,38,39].

Figure 3

Overview of the energy flux density (mJ/mm²) related to the underlying target mechanism. Abbreviations: TGF = transforming growth factor, PDGF = platelet-derived growth factor, VEGF = vascular endothelial growth factor, IGF = insulin-like growth factor, IL = interleukin, PCNA = proliferating cell nuclear antigen, MAPK = mitogen-activated protein kinase, TLR = toll-like receptor, αSMA = alpha-smooth muscle actin, MMP = matrix metalloprotease, Cbfα = core binding factor alpha, GADPH = glyceraldehyde 3-phosphate dehydrogenase, OCN = osteocalcin, PPARϒ = peroxisome proliferator-activated receptor gamma, Erk = extracellular signal-regulated kinase.

Figure 4

Overview of the effect of SWT on inflammation (a), proliferation (b), differentiation (c) and apoptosis (d) phase. Abbreviations: αSMA = alpha-smooth muscle actin, SOCS3 = suppressor of cytokine signaling, HLA DR = human leukocyte antigen-DR, CD = cluster of differentiation, CK = cytokine, GF = growth factor, IL = interleukin, PDGF = platelet-derived growth factor, TGF = transforming growth factor, VEGF = vascular endothelial growth factor, TNFα = tumor necrosis factor, NK = natural killer, MAPK = mitogen-activated protein kinase, YAP = yes associated protein, WST = water-soluble tetrazolium salts, CXCL = chemokine ligand, MMP = matrix metalloprotease, Cbfα = core-binding factor, FAK/Erk = focal adhesion kinase, pSTAT = signal transducers and activators transcription.