The Molecular Mechanisms of Systemic Sclerosis-Associated Lung Fibrosis

Abstract

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disorder that affects the connective tissues and has the highest mortality rate among the rheumatic diseases. One of the hallmarks of SSc is fibrosis, which may develop systemically, affecting the skin and virtually any visceral organ in the body. Fibrosis of the lungs leads to interstitial lung disease (ILD), which is currently the leading cause of death in SSc. The identification of effective treatments to stop or reverse lung fibrosis has been the main challenge in reducing SSc mortality and improving patient outcomes and quality of life. Thus, understanding the molecular mechanisms, altered pathways, and their potential interactions in SSc lung fibrosis is key to developing potential therapies. In this review, we discuss the diverse molecular mechanisms involved in SSc-related lung fibrosis to provide insights into the altered homeostasis state inherent to this fatal disease complication.

Keywords: fibroblast; fibrosis; interstitial lung disease; lung; molecular mechanisms; pulmonary; scleroderma; systemic sclerosis.

Figure 1

Lung fibrosis in SSc is the result of an imbalance between anti-fibrotic and pro-fibrotic factors, favoring the latter, and resulting in the activation of fibroblasts and the excessive deposition of ECM. ES, endostatin; MMP, matrix metalloproteinase; CTSL, Cathepsin L; TGFβ, Transforming Growth Factor Beta; PDGF, Platelet-Derived Growth Factor; WNT, Wingless-Related Integration Site; ECM, extracellular matrix; SSc, systemic sclerosis.