Mechanisms of fibrosis: therapeutic translation for fibrotic disease

Abstract

Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases.

Lung Pericytes and Resident Fibroblasts

“…13,53 Most potential therapeutic agents, including the first two approved to treat IPF, have targets important to myofibroblasts. 64,89,90 The most direct approach for drug development has been to inhibit key growth and developmental factors or their receptors, later joined by strategies focused on extracellular matrix structure, stress, and metabolism. Immunosuppression might be considered an indirect approach and potential risk, especially in diseases where leukocytes do not seem a primary concern.…”

Mechanisms of Lung Fibrosis Resolution

“…94 Macrophages are almost always found in close proximity with collagen-producing myofibroblasts, and are believed to contribute and sustain a fibroproliferative lung microenvironment through their expression of profibrotic genes. 92 The presence of these alternatively activated macrophages has been linked to acute exacerbation of IPF patients consistent with the idea that macrophages can modulate the stability or progression of IPF.…”

“…Identifying the signals that regulate macrophage phenotypic conversion, differentiation, or recruitment may provide methods to influence the beneficial aspects of inflammation to impede progression or reverse ongoing disease. 94 …”

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

“…1 Chronic tissue injury as in cases of unresolved infection, inflammatory disease, or cancer can often lead to fibrosis. 2 In SSc, these remodeling processes appear to proceed unchecked over years, yet the fundamental driver of the pathology remains unknown. Considerable attention has focused on transforming growth factor (TGF)-betriggered conversion of mesenchymal lineage cells to a-smooth muscle actin (SMA)epositive myofibroblasts as the central event in fibrosis.…”