Fibrosis is scarring and tissue hardening caused by the excess deposition of extracellular matrix (ECM) proteins by myofibroblasts in response to chronic inflammation. A variety of noxious stimuli—including toxins, infectious pathogens, autoimmune reactions, and mechanical stress—are able to induce a fibrotic cellular response. Fibrosis can affect all tissues of the body, and left unchecked, can result in organ failure and death. Current research on key signaling pathways that regulate fibrogenesis has identified potential therapeutic targets of interest to stem the progression of fibrosis and restore cellular function.
In response to tissue damage, myofibroblasts—derived from a number of sources including resident fibroblasts, mesenchymal cells, circulating fibrocytes, and the transdifferentiation of other cell types—initiate a wound healing response by remodeling the extracellular environment to restore tissue integrity and promote the replacement of parenchymal cells. Normally, this pro-fibrotic program is turned off as the tissue heals. However, persistent insult and injury results in dysregulation of this process, leading to pathologically excessive deposition of ECM proteins and, in concert with upregulated myofibroblast activity, creates a chronic inflammatory environment with macrophage and immune cell infiltration. In this cellular milieu, cytokines and growth factors are abundantly released, including transforming growth factor-beta (TGF-β) family members and Wingless/Int-1 (Wnt1) which act as the principal effectors of the fibrotic process. TGF-β and Wnt1 bind to their cognate cell surface receptors and initiate downstream signaling—ultimately leading to the nuclear translocation of Smad2/3 and CBP/β-Catenin transcriptional modulators, respectively. This results in the upregulated expression of target genes that function to further enhance myofibroblast differentiation and the production and secretion of ECM proteins including collagen, laminin, and fibronectin.
As excessive ECM deposition progresses, the structure of the matrix alters and becomes stiff. ECM tension is sensed by cells through mechanotransduction via cell surface integrin receptors which activate the Hippo signaling pathway and its primary downstream effectors YAP and TAZ. In yet another feed forward loop, activated YAP and TAZ translocate to the nucleus and contribute to the upregulation of profibrotic genes—including CTGF and PDGF—which promote myofibroblast proliferation and activation via the PI3K/AKT/mTOR pathway.
Despite varied cellular insults and tissue contexts, these outlined mechanisms are hallmarks of fibrosis in a range of diseases. Examples of conditions associated with pathological fibrosis include non-alcoholic steatohepatitis (NASH) and its precursor non-alcoholic fatty liver disease (NAFLD), both conditions that can lead to liver failure. Other examples include idiopathic pulmonary fibrosis (IPF), alcoholic liver disease (ALD), and renal fibrosis. In addition to organ damage, fibrosis has been implicated in cancer progression, as the fibrotic ECM can stimulate cellular proliferation and alter cell polarity—contributing to tumor development and growth.
Targeting fibrosis to treat disease remains a challenging prospect since the inflammatory response, which leads to harmful ECM deposition and scarring, is also required for beneficial reparative processes. Further elucidation of the cellular and molecular mechanisms underlying fibrosis are required to develop therapies capable of separating these disparate effects and ultimately translate to positive clinical outcomes for patients.
created October 2019
