Fibrosis in systemic sclerosis

Abstract

This article reviews current understanding of the pathophysiology of fibrosis in systemic sclerosis. It highlights recent discoveries, insights, and emerging research, and potential opportunities for the development of targeted antifibrotic therapies.

Fig. 1

Histology of skin and lung fibrosis: diffuse cutaneous systemic sclerosis. (Top left panel) Dense skin fibrosis with increased extracellular matrix deposition in the dermis. (Top right panel) Late stage disease. Secondary structures within the skin such as hair follicles and sweat glands are reduced, and rete pegs are flattened. H&E stain. (Bottom panels) Lung tissue from systemic sclerosis. Masson’s trichrome staining shows progression of fibrosis.

Fig. 2

The pathogenetic triad of systemic sclerosis. The pathogenesis of systemic sclerosis involves autoimmunity, vasculopathy, and fibrosis. Both autoimmunity and vasculopathy appear to precede the onset, and contribute to the progression of fibrosis. Vascular injury and fibrosis, in turn, enhance and sustain chronic autoimmunity and inflammation.

Fig. 3

Fibroblast accumulation in fibrosis. Activated fibroblasts produce collagen and other connective tissue molecules, and contract and remodel their extracellular matrix. Fibroblast accumulation in lesional fibrotic tissue reflects activation and proliferation of resident cells, transdifferentiation and persistence of myofibroblasts, and recruitment and differentiation of bone marrow-derived circulating fibrocytes and mesenchymal progenitor cells, and potentially, plasticity of epithelial cells. (Data from Varga J, Abraham DJ. Systemic sclerosis: paradigm multisystem fibrosing disorder. J Clin Invest 2007;117(3):557–67.)

Fig. 4

TGF-β signaling in fibroblasts: Smad and non-Smad pathways. TGF-β activates cell surface TGF-β receptors TβR1 and TβR2, resulting in phosphorylation of downstream targets, such as Smads. Activated Smad2 and Smad3 form a complex with Smad4, and transit from the cytoplasm into the nucleus, bind to conserved DNA sequences and activate (or repress) transcription. Transcriptional cofactors provide tissue and gene specificity (top panel). In addition to this canonical TGF-β signal transduction mechanism, TGF-β also can activate complex Smad-independent intracellular kinase cascades that are involved in specific TGF-β responses (bottom panel). (Data from Varga J, Abraham DJ. Systemic sclerosis: paradigm multisystem fibrosing disorder. J Clin Invest 2007;117(3):557–67.)