Tyrosine kinases in the pathogenesis of tissue fibrosis in systemic sclerosis and potential therapeutic role of their inhibition

Abbreviation: BCR = Breakpoint Cluster Region protein; c-Abl = Cytoplasmic Abelson Kinase; CD40L = CD-40 Ligand; CML = Chronic Myeloid Leukemia; CXCL-4 = CxC Motif Ligand 4; DDR = Discoidin Domain receptors; ECM = Extracellular Matrix; EndoMT = Endothelial-Mesenchymal Transdifferentiation; EphRs = Ephrin Receptors; FGF = Fibroblast Growth Factor; FVC = Forced Vital Capacity; GI = Gastrointestinal; ILD = Interstitial Lung Disease; JAK/STAT = Janus kinases/ Signal Transducer and Activator of Transcription; IPF = Idiopathic Pulmonary Fibrosis; mRSS = Modified Rodnan Skin Score; NRTKs = Non-Receptor-Activated Tyrosine Kinases; PAH = Pulmonary Arterial Hypertension; PDGF = Platelet-Derived Growth actor; PKCd = Protein Kinase C Systemic sclerosis (SSc) is an idiopathic autoimmune disease with a heterogeneous clinical phenotype ranging from limited cutaneous involvement to rapidly progressive diffuse SSc. The most severe SSc clinical and pathologic manifestations result from an uncontrolled fibrotic process involving the skin and various internal organs. The molecular mechanisms responsible for the initiation and progression of the SSc fibrotic process have not been fully elucidated. Recently it has been suggested that tyrosine protein kinases play a role. The implicated kinases include receptor-activated tyrosine kinases and nonreceptor tyrosine kinases. The receptor kinases are activated following specific binding of growth factors (platelet-derived growth factor, fibroblast growth factor, or vascular endothelial growth factor). Other receptor kinases are the discoidin domain receptors activated by binding of various collagens, the ephrin receptors that are activated by ephrins and the angiopoetin-Tie-2s receptors. The nonreceptor tyrosine kinases c-Abl, Src, Janus, and STATs have also been shown to participate in SScassociated tissue fibrosis. Currently, there are no effective disease-modifying therapies for SSc-associated tissue fibrosis. Therefore, extensive investigation has been conducted to examine whether tyrosine kinase inhibitors (TKIs) may exert antifibrotic effects. Here, we review the role of receptor and nonreceptor tyrosine kinases in the pathogenesis of the frequently progressive cutaneous and systemic fibrotic alterations in SSc, and the potential of TKIs as SSc disease-modifying antifibrotic therapeutic agents. (Translational Research 2021; 231:139-158)

Automated summary

Systemic sclerosis is an autoimmune disease characterized by uncontrolled fibrotic processes involving skin and internal organs. The molecular mechanisms behind the disease are not fully understood, but tyrosine protein kinases, including both receptor-activated and nonreceptor tyrosine kinases, are believed to play a role.