The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival time from diagnosis of 2-3 years. Although the pathogenic pathways have not been fully elucidated, IPF is believed to be caused by persistent epithelial injury in genetically susceptible individuals. Tyrosine kinases are involved in a range of signalling pathways that are essential for cellular homeostasis. However, there is substantial evidence from in vitro studies and animal models that receptor tyrosine kinases, such as the platelet-derived growth factor receptor, vascular endothelial growth factor receptor and fibroblast growth factor receptor, and non-receptor tyrosine kinases, such as the Src family, play critical roles in the pathogenesis of pulmonary fibrosis. For example, the expression and release of tyrosine kinases are altered in patients with IPF, while specific tyrosine kinases stimulate the proliferation of lung fibroblasts in vitro. Agents that inhibit tyrosine kinases have shown anti-fibrotic and anti-inflammatory effects in animal models of pulmonary fibrosis. Recently, the tyrosine kinase inhibitor nintedanib has shown positive results in two phase III trials in patients with IPF. Here, we summarise the evidence for involvement of specific tyrosine kinases in the pathogenesis of IPF and the development of tyrosine kinase inhibitors as treatments for IPF.
Dept of Hematology/Oncology, University Hospital of Giessen and Marburg, Marburg, Germany.
Friedrich
F
Grimminger
Dept of Pulmonary and Critical Care Medicine, ILD Program, University Hospital of Giessen and Marburg, Marburg, Germany.
Andreas
A
Günther
"Regional Centre for Rare Lung Diseases", Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
Carlo
C
Vancheri
D000818:Animals; D002986:Clinical Trials as Topic; D018450:Disease Progression; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology* / Q000401:mortality*; D008171:Lung Diseases / Q000201:enzymology / Q000401:mortality; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D019061:src-Family Kinases