Epithelial injury induces an innate repair mechanism linked to cellular senescence and fibrosis involving IGF-binding protein-5.
Fibrosis is associated with epithelial repair. It involves the activation of fibroblasts, increased production of extracellular matrix proteins and transdifferentiation to contractile, myofibroblasts that aid in wound contraction. This provisional matrix plugs the injured epithelium and provides a scaffold for epithelial cell migration, involving an epithelial-mesenchymal transition (EMT). When epithelial injury involves blood loss, this leads to platelet activation, the production of several growth factors and an acute inflammatory response. Under normal circumstances, the epithelial barrier is repaired and the inflammatory response resolves. However, in fibrotic disease, the fibroblast response continues, resulting in unresolved wound healing. The fibrotic diseases range from scleroderma, where the problem may be restricted to the skin and where it is not life-threatening, through to systemic forms that can manifest as, for example, idiopathic pulmonary fibrosis, in which death is inevitable within 3-5 years. Anti-inflammatory treatments have failed to ameliorate the disease condition and focus has instead turned to transforming growth factor-beta1 (TGFB1), since it induces many of the processes involved, including fibroblast activation and EMT. Most recently, however, a new player in this process has been described, IGF-binding protein-5 (IGFBP5). IGFBP5 has also been shown to induce similar effects to TGFB1, but, in addition, it is strongly implicated in the process of senescence which is now believed to be a significant factor in these diseases. We examine the evidence for this role of IGFBP5 and identify some of the therapeutic targets which might be used to ameliorate these diseases of unknown cause.
Allan
Gordon J
GJ
SIPBS, University of Strathclyde, Glasgow G11XW, UK.
Beattie
James
J
Flint
David J
DJ
D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D004848:Epithelium / Q000473:pathology*; D005355:Fibrosis / Q000378:metabolism*; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000473:pathology; D008954:Models, Biological
D018975:Insulin-Like Growth Factor Binding Protein 5