Role of Growth Factors in the Pathogenesis of Tissue Fibrosis in Systemic Sclerosis

Jimenez, Sergio A.; Castro, Susan V; Piera-Velázquez, Sonsoles

doi:10.2174/157339710793205611

Cited by 25 publications

(16 citation statements)

References 144 publications

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“…The TGF-β family of proteins comprises several pleiotropic growth factors that play crucial roles in numerous physiological processes including embryogenesis, cellular development and differentiation, immunologic system development, inflammatory response functions, and wound repair [ 71 , 72 ]. Owing to their potent profibrotic effects these molecules have also been implicated in the pathogenesis of various fibrotic human diseases [ 73 , 74 , 75 , 76 , 77 , 78 ]. TGF-β1, the most well studied member of this protein family is the most potent profibrogenic growth factor identified to date.…”

Section: Pathways Involved In Tissue Fibrosis Participate In the Mmentioning

confidence: 99%

Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases

Piera-Velázquez

Mendoza

Jiménez

2016

JCM

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222

207

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Fibrotic diseases encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis, sclerodermatous graft versus host disease, nephrogenic systemic fibrosis, and IgG4-associated sclerosing disease, as well as numerous organ-specific disorders including radiation-induced fibrosis, and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrous tissue macromolecules in affected organs leading to their dysfunction and ultimate failure. The pathogenesis of fibrotic diseases is complex and despite extensive investigation has remained elusive. Numerous studies have identified myofibroblasts as the cells responsible for the establishment and progression of the fibrotic process. Tissue myofibroblasts in fibrotic diseases originate from several sources including quiescent tissue fibroblasts, circulating CD34+ fibrocytes, and the phenotypic conversion of various cell types including epithelial and endothelial cells into activated myofibroblasts. However, the role of the phenotypic transition of endothelial cells into mesenchymal cells (Endothelial to Mesenchymal Transition or EndoMT) in the pathogenesis of fibrotic disorders has not been fully elucidated. Here, we review the evidence supporting EndoMT’s contribution to human fibrotic disease pathogenesis.

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Section: Pathways Involved In Tissue Fibrosis Participate In the Mmentioning

confidence: 99%

Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases

Piera-Velázquez

Mendoza

Jiménez

2016

JCM

Self Cite

222

207

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“…Pro-fibrotic cytokines and growth factors including TGF-β, PDGF, endothelin-1, and CTGF, and other mediators known to induce increased proliferation of smooth muscle cells, subendothelial accumulation of fibrous tissue, and fibroblast activation in the skin and in the parenchyma of various organs, have been shown to participate in various aspects of SSc-associated fibrotic pathways [62–67,71–73]. …”

Section: Pathophysiologymentioning

confidence: 99%

Treatment of rapidly progressive systemic sclerosis: current and futures perspectives

Mendoza

Mansoor

Jimenez

2015

Expert Opinion on Orphan Drugs

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Introduction Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by severe and often progressive cutaneous, pulmonary, cardiac and gastrointestinal tract fibrosis, cellular and humoral immunologic alterations, and pronounced fibroproliferative vasculopathy. There is no effective SSc disease modifying therapy. Patients with rapidly progressive SSc have poor prognosis with frequent disability and very high mortality. Areas Covered This paper reviews currently available therapeutic approaches for rapidly progressive SSc and discuss novel drugs under study for SSc disease modification. Expert Opinion The extent, severity, and rate of progression of SSc skin and internal organ involvement determines the optimal therapeutic interventions for SSc. Cyclophosphamide for progressive SSc-associated interstitial lung disease and mycophenolate for rapidly progressive cutaneous involvement have shown effectiveness. Methotrexate has been used for less severe skin progression and for patients unable to tolerate mycophenolate. Rituximab was shown to induce improvement in SSc-cutaneous and lung involvement. Autologous bone marrow transplantation is reserved for selected cases in whom poor survival risk outweighs the high mortality rate of the procedure. Novel agents capable of modulating fibrotic and inflammatory pathways involved in SSc pathogenesis, including tocilizumab, pirfenidone, tyrosine kinase inhibitors, lipid lysophosphatidic acid 1, and NOX4 inhibitors are currently under development for the treatment of rapidly progressive SSc.

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“…Numerous studies have shown that tissue fibrosis in SSc is the result of an upregulated expression of genes encoding collagen and other extracellular matrix proteins in affected organs. The exact mechanisms responsible for the establishment of the fibrotic process in SSc have not been precisely determined [2–6], although it has become very clear that several growth factors play a crucial role [166]. …”

Section: Molecular Mechanisms Of Endomtmentioning

confidence: 99%

Role of Endothelial to Mesenchymal Transition in the Pathogenesis of the Vascular Alterations in Systemic Sclerosis

2013

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The pathogenesis of Systemic Sclerosis (SSc) is extremely complex, and despite extensive studies, the exact mechanisms involved are not well understood. Numerous recent studies of early events in SSc pathogenesis have suggested that unknown etiologic factors in a genetically receptive host trigger structural and functional microvascular endothelial cell abnormalities. These alterations result in the attraction, transmigration, and accumulation of immune and inflammatory cells in the perivascular tissues, which in turn induce the phenotypic conversion of endothelial cells and quiescent fibroblasts into activated myofibroblasts, a process known as endothelial to mesenchymal transition or EndoMT. The activated myofibroblasts are the effector cells responsible for the severe and frequently progressive fibrotic process and the fibroproliferative vasculopathy that are the hallmarks of SSc. Thus, according to this hypothesis the endothelial and vascular alterations, which include the phenotypic conversion of endothelial cells into activated myofibroblasts, play a crucial role in the development of the progressive fibrotic process affecting skin and multiple internal organs. The role of endothelial cell and vascular alterations, the potential contribution of endothelial to mesenchymal cell transition in the pathogenesis of the tissue fibrosis, and fibroproliferative vasculopathy in SSc will be reviewed here.

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Role of Growth Factors in the Pathogenesis of Tissue Fibrosis in Systemic Sclerosis

Cited by 25 publications

References 144 publications

Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases

Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases

Treatment of rapidly progressive systemic sclerosis: current and futures perspectives

Role of Endothelial to Mesenchymal Transition in the Pathogenesis of the Vascular Alterations in Systemic Sclerosis

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