Pathogenesis of systemic sclerosis: recent insights of molecular and cellular mechanisms and therapeutic opportunities

Abstract

that results in irreversible scarring and organ failure. In other word, fibrosis is the end-result of a cascade of vascular and immune responses to environmental injury, and represents a failed tissue repair process. There have been advances in understanding of pathogenic processes that reflect the interplay between immune-inflammatory processes and vasculopathy and fibrosis. This review focuses on recent insights of functional consequences of SSc, highlighting three major characteristics of SSc; microvasculopathy, excessive fibrosis, and immune dysregulation. Microvasculopathy Although, widespread structural changes of the microvasculature are well documented in SSc patients, many aspects of SSc vasculopathy, including the nature of the injury and the fate of injured endothelial cells (ECs), remain poorly understood. Nevertheless, studies in recent years have brought a wealth of new information on the molecular and cellular mechanisms contributing to SSc vasculopathy. Diverse triggers have been implicated in inducing EC damage, including infection, immune-mediated cytotoxicity, anti-endothelial autoantibodies (AECAs), and ischemia-reperfusion injury. The resulting pathogenic changes in ECs may also vary and may include EC apoptosis, endothelial to mesenchymal transition (EndoMT), and other forms of EC activation. A bi-directional

Significance of the angiotensin I/angiotensin II/angiotensin‐(1‐7) axis in the pathogenesis of systemic sclerosis

“…17 Ang II together with endothelin-1 are supposed to promote endothelial mesenchymal transition, therefore promoting systemic fibrosing. 7 Subcutaneous infusion of Ang II was shown by Stawski et al 18 the main target receptor for Ang II, had been previously identified in patients with SSc and linked to increased prevalence of both vascular and fibrotic complications with the higher risk of SSc-related mortality. 7 The significantly elevated serum level of Ang II was found by Kawaguchi et al 4 A discovery of Ang-(1-7) in 1991 revealed a counterbalancing axis in the renin-angiotensin system.…”

“…7 Subcutaneous infusion of Ang II was shown by Stawski et al 18 the main target receptor for Ang II, had been previously identified in patients with SSc and linked to increased prevalence of both vascular and fibrotic complications with the higher risk of SSc-related mortality. 7 The significantly elevated serum level of Ang II was found by Kawaguchi et al 4 A discovery of Ang-(1-7) in 1991 revealed a counterbalancing axis in the renin-angiotensin system. This novel angiotensin was produced directly by degradation of Ang II or indirectly from Ang I, and it manifested itself with a wide spectrum of beneficial effects in CVS.…”

“…Ang II was later found to exert vasoconstrictive, proinflammatory and profibrotic activity . Ang II together with endothelin‐1 are supposed to promote endothelial mesenchymal transition, therefore promoting systemic fibrosing . Subcutaneous infusion of Ang II was shown by Stawski et al .…”

“…to induce scleroderma‐like skin thickening in experimental mice study. Agonistic autoantibodies aimed against AT 1 R, the main target receptor for Ang II, had been previously identified in patients with SSc and linked to increased prevalence of both vascular and fibrotic complications with the higher risk of SSc‐related mortality …”

“…Both Ang II and Ang‐(1‐7) are derived directly or indirectly from Ang I, but they exert opposite effects in the cardiovascular system (CVS). Ang II is known to cause a dysfunction of endothelial cells and vasoconstriction, or endothelial mesenchymal transition, whereas Ang‐(1‐7) manifests a wide spectrum of beneficial effects in the blood circulation . It is an evident that some disturbances in a metabolic pathway of Ang II and Ang‐(1‐7) may occur in SSc, but their significance in the pathogenesis of the disease stays unclear due to discrepancies of previous studies …”