Fibrosis—a lethal component of systemic sclerosis

Abstract

Fibrosis is a pathological process characterized by excessive accumulation of connective tissue components in an organ or tissue. Fibrosis is produced by deregulated wound healing in response to chronic tissue injury or chronic inflammation, the hallmarks of rheumatic diseases. Progressive fibrosis, which distorts tissue architecture and results in progressive loss of organ function, is now recognized to be one of the major causes of morbidity and mortality in individuals with one of the most lethal rheumatic disease, systemic sclerosis (SSc). In this Review, we discuss the pathological role of fibrosis in SSc. We discuss the involvement of endothelium and pericyte activation, aberrant immune responses, endoplasmic reticulum stress and chronic tissue injury in the initiation of fibrosis in SSc. We then discuss fibroblast activation and myofibroblast differentiation that occurs in response to these initiating processes and is responsible for excessive accumulation of extracellular matrix. Finally, we discuss the chemical and mechanical signals that drive fibroblast activation and myofibroblast differentiation, which could serve as targets for new therapies for fibrosis in SSc.

Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma

“…The origins of fibrotic myofibroblasts, and the cues and mechanisms involved in their transdifferentiation and persistence, have been the subject of controversy, with data deriving largely from various animal models of organ fibrosis and differing among distinct types of organ fibrosis 5 ; nevertheless, the fundamental pathogenic roles of transforming growth factor-b (TGF-b), Wnt/b-catenin, and cytokines, such as IL-13, oxidative stress, and biomechanical signals, across multiple types of organ fibrosis are supported by substantial experimental evidence. 6 …”

The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway

“…PPARγ expression is reduced in SSc lung [100,181]. In SSc, fibroblasts synthesize excessive collagen and profibrotic molecules such as integrins, receptors for TGF-β1 and αSMA [191,192]. PPARγ expression is diminished in SSc skin fibroblast [100,193,194].…”

The indicators of general clinical methods as prognostic markers of the severity of systemic scleroderma complicated by the development of pneumosclerosis.

“…Заміщення легеневої тканини на сполучну є незворотним процесом [3,6]. Саме тому до-слідження патогенетичних механізмів розвитку пневмосклерозу задля своєчасного встановлення діагнозу і лікування патології, яка призвела до розвитку пневмосклерозу та наступної дихальної недостатності, є завданням актуальним [2,4].…”