Regulation of PDGF and its receptors in fibrotic diseases
Introduction
Fibrotic diseases occur in a variety of organ systems including lung, liver, kidney, intestine, heart, skin and bone marrow. In all of these fibrotic reactions, the underlying mechanism involves the proliferation of mesenchymal cells possessing a myofibroblast phenotype and the subsequent deposition of collagen and other extracellular matrix proteins by these cells leading to progressive scarring and loss of organ function. In general, fibrogenesis is a response to tissue injury and many of the same factors that mediate tissue repair also promote a fibrogenesis. Therefore, understanding which factors are aberrantly expressed is paramount to developing treatment strategies for fibrotic diseases. Several polypeptide mediators are central to the fibrotic process, including PDGF and TGF-β1. PDGF is a potent mitogen for cells of mesenchymal origin, including myofibroblasts, while TGF-β1 primarily functions in fibrogenesis to stimulate collagen deposition by newly replicated myofibroblasts.
PDGF-A and -B chain dimeric isoforms (PDGF-AA, -AB, and -BB) play important roles in the pathogenesis of fibrosis. These isoforms promote myofibroblast proliferation and chemotaxis, but also serve other functions including stimulation of collagen production and promotion of cell adhesion. PDGF-AA binds selectively to the PDGFRα, while PDGF-B chain isoforms bind and dimerize both PDGFRα and PDGFRβ [1]. Less is known regarding the significance of the more recently discovered PDGF-C and PDGF-D isoforms to fibrogenesis, which are protease-activated isoforms that bind to the PDGFRα and the PDGFRβ, respectively. PDGF activity is also regulated by a variety of extracellular proteins, glycoproteins, and extracellular matrix molecules that are increased during the fibrogenic process [2].
There is currently no effective treatment for fibrotic diseases, with the exception of certain fibrotic liver diseases. In general, severe scarring of tissues that accompanies end stage fibrosis is thought to be irreversible in most cases. Moreover, anti-inflammatory drugs do little to prevent or treat fibrosis in clinical settings. Therefore, it is most reasonable to intervene with myofibroblast replication, which precedes the deposition of the extracellular matrix molecules that define the fibrotic lesion. Because PDGF and its receptors are major mediators of myofibroblast growth and survival, it is anticipated that PDGF receptor tyrosine kinase inhibitors will prove effective in the development of a therapeutic strategy for the treatment of fibrotic diseases.
Section snippets
Pulmonary fibrosis
Fibrotic interstitial lung diseases involve the proliferation of myofibroblasts in the interstitium, including the alveolar walls and perivascular and peribronchial tissues. These include the chronic progressive disorders such as idiopathic pulmonary fibrosis (IPF) and a number of fibrotic diseases that occur as a result of environmental exposure, including asbestosis [3]. These chronic diseases are thought to arise from prolonged, low-grade injury that feature smoldering lesions within the
Liver fibrosis
Hepatic fibrogenesis occurs following injury to the liver by a variety of causes, including autoimmune, alcohol or drug induced, cholestatic and metabolic diseases, and viral hepatitis [58]. Liver cirrhosis is the end stage consequence of fibrosis of the hepatic parenchyma, yet reversal of cirrhosis is often possible [59]. The underlying cellular mechanisms involved in hepatic fibrogenesis principally involve the activation of hepatic stellate cells, the principal fibrogenic cell type in liver.
Scleroderma
Scleroderma, also known as systemic sclerosis, is an autoimmune disease characterized by vascular damage and progressive dermal fibrosis [83]. Fibrotic reactions not only occur in skin, but also develop in many internal organs including lung, heart, gastrointestinal tract, and kidneys [83], [84]. In particular, pulmonary fibrosis occurs in up to seventy percent of scleroderma patients [85]. Dermal and lung fibroblasts from patients with scleroderma differ from normal fibroblasts and numerous
Renal fibrosis
The most common causes of renal failure are the fibrotic diseases diabetic nephropathy and glomerulonepthritides. The glomerulonephritides include IgA nephropathy, membranoproliferative glomerulonephritis, idiopathic focal sclerosis, and lupus nephritis [103]. These progressive renal fibroproliferative diseases are characterized by glomerular mesangial cell proliferation and matrix accumulation [104]. Renal mesangial cell growth is driven to a large extent by PDGF. The expression of PDGF
Intestinal fibrosis
Intestinal subepithelial myofibroblasts and interstitial cells of Cajal are the two types of myofibroblasts that play a fundamental role the progression of intestinal fibrosis [138]. These collagen-producing connective tissue cells are thought to be central effector cells in mediating the disease progression of Crohn’s disease and collagenous colitis. PDGF-BB is expressed in the colonic mucosa [139], and intestinal myofibroblasts are activated and undergo mitogenesis and chemotaxis in response
PDGF modulation by binding proteins and matrix molecules
As discussed previously, the biologic responses to PDGF isoforms are determined by the expression of their high-affinity cell-surface signaling receptors. However, considerable modulation of growth factor action can be achieved by through the interaction with extracellular proteins that represent low-affinity docking sites or reservoirs for growth factors. These proteins include the proteinase inhibitor alpha-2-macroglobulin (α2M), and several component of the extracellular matrix including
PDGF and PDGF receptors as therapeutic targets in fibrosis
Effective strategies for the treatment of fibrotic diseases are lacking in most instances. Fibrogenesis can be prevented or even reversed in the liver in some cases. For example, hepatic fibrosis caused by hepatitis C virus can be reversed with antiviral drugs and α-interferon [169]. However, there is currently no effective treatment strategy available for patients with pulmonary fibrotic diseases [170]. In all fibrotic diseases, myofibroblasts are the principal collagen-producing cell type
Summary and conclusions
PDGF appears to play an essential role in promoting the growth and survival of myofibroblasts in all types of fibrotic diseases. However, significant variations in PDGF and PDGF receptor regulation exist from one organ to another. For example, PDGFRα up-regulation in the lung drives myofibroblast hyper-proliferation, whereas induction of the PDGFRβ is paramount in mediating the PDGF growth response in hepatic stellate cells, which are the myofibroblast counterpart in the liver. TGF-β1
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