Abstract
A considerable amount of research time has been invested in studies aimed at elucidating pathogenic processes in systemic sclerosis (SSc). Despite this, major challenges for biomedical science remain, such as identification of the key factors that determine susceptibility to SSc, and elucidation of the precise nature of the initiating event that causes endothelial cell injury and ultimately brings about the biological cascade(s) that lead to the pathologic vascular changes. Involved factors are likely to include genetic perturbations, environmental cues, tissue injury, infection and hypoxia/oxidative stress. As important as determining the initiating events are the identification and characterization of key factors that are functionally important in driving vascular disease progression, because these factors are potential targets for therapeutic intervention. This article reviews the role of endothelin as an example of a pleiotropic mediator with effects on various aspects of SSc pathogenesis, such as inflammation, vasculopathy and tissue remodelling.
Highlights
In order to understand the initiators of endothelial injury and how the ensuing vascular dysfunction contributes to the development of systemic sclerosis (SSc), it is necessary to consider the normal biology of the endothelium and of the myriad of biological molecules and biological functions under its control, and to assess which specific processes are dysregulated in disease
Through induction of intercellular adhesion molecule (ICAM)-1, ET-1 activates adhesion molecule expression, which may be important in regulating the inflammatory response that occurs in the early stages of SSc
It is well accepted that endothelin plays a major role in vasoconstriction, and it is an important mediator in extracellular matrix (ECM) remodelling and deposition
Summary
In order to understand the initiators of endothelial injury and how the ensuing vascular dysfunction contributes to the development of systemic sclerosis (SSc), it is necessary to consider the normal biology of the endothelium and of the myriad of biological molecules and biological functions under its control, and to assess which specific processes are dysregulated in disease. Classical and MMPactivated endothelin can induce gene transcription and result in the familiar cellular changes of fibrosis, matrix deposition and tissue remodelling that are observed in SSc. As well as matrix production and remodelling, SSc is characterized by an early inflammatory response that involves increased leucocyte infiltration to affected tissues and elevated leucocyte-fibroblast interactions. ET-1 can play a proinflammatory role, and is able to turn on ICAM-1 gene expression and cause an increase in leucocyte-fibroblast interaction This upregulation of fibroblast ICAM-1 was found to be potently inhibited by the dual endothelin receptor antagonist bosentan and specific inhibitors of ET-1dependent signalling pathways [31]. Data obtained far in the context of SSc support the notion that ET-1 can play an important role in a number of relevant pathological processes, including inflammation, vasculopathy, tissue remodelling and fibrosis This places ET-1 as a key mediator in this disease. Likewise, blocking critical mediators such as ET-1, TGF-β and certain chemokines such as monocyte chemoattractant protein-1 may likewise be effective in preventing the progression of fibrotic diseases such as SSc
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