LAUSR

Fibrosis is defined as an excessive deposition of connective tissue components and can affect virtually every organ system, including the skin, lungs, liver and kidney. Fibrotic tissue remodelling often leads to organ malfunction and is commonly associated with high morbidity and mortality. The medical need for effective antifibrotic therapies is thus very high. However, the extraordinarily high costs of drug development and the rare incidence of many fibrotic disorders hinder the development of targeted therapies for individual fibrotic diseases. A potential strategy to overcome this challenge is to target common mechanisms and core pathways that are of central pathophysiological relevance across different fibrotic diseases. The factors influencing susceptibility to and initiation of these diseases are often distinct, with disease-specific and organ-specific risk factors, triggers and sites of first injury. Fibrotic remodelling programmes with shared fibrotic signalling responses such as transforming growth factor-β (TGFβ), platelet-derived growth factor (PDGF), WNT and hedgehog signalling drive disease progression in later stages of fibrotic diseases. The convergence towards shared responses has consequences for drug development as it might enable the development of general antifibrotic compounds that are effective across different disease entities and organs. Technological advances, including new models, single-cell technologies and gene editing, could provide new insights into the pathogenesis of fibrotic diseases and the development of drugs for their treatment. A number of core pathways and mechanisms of fibrosis, outlined in this Review, are shared across different tissues and might therefore present targets for general antifibrotic strategies. Organ-specific and disease-specific differences in fibrotic diseases could also provide insights for drug development efforts. In fibrotic diseases, disease-specific triggers initiate site-specific injuries, which activate distinct cells that drive fibrosis in a genetically susceptible individual.The inflammatory responses vary across different fibrotic conditions but share polarization towards a T helper 2 cell–M2 macrophage-mediated response, with abundant release of profibrotic mediators as a common feature.Although myofibroblasts are a heterogeneous population of cells that are derived from various cellular precursors, they are activated by a shared set of core pathways, including transforming growth factor-β, platelet-derived growth factor, WNT and hedgehog signalling.Structural changes in fibrotic tissues, such as tissue stiffness and hypoxia, generate an important feed-forward loop that leads to chronicity of tissue-repair responses in fibrotic diseases.The chronic profibrotic milieu induces epigenetic imprinting in myofibroblasts, which serves as a self-amplifying loop to consolidate fibroblast activation in the later stages of fibrotic diseases. In fibrotic diseases, disease-specific triggers initiate site-specific injuries, which activate distinct cells that drive fibrosis in a genetically susceptible individual. The inflammatory responses vary across different fibrotic conditions but share polarization towards a T helper 2 cell–M2 macrophage-mediated response, with abundant release of profibrotic mediators as a common feature. Although myofibroblasts are a heterogeneous population of cells that are derived from various cellular precursors, they are activated by a shared set of core pathways, including transforming growth factor-β, platelet-derived growth factor, WNT and hedgehog signalling. Structural changes in fibrotic tissues, such as tissue stiffness and hypoxia, generate an important feed-forward loop that leads to chronicity of tissue-repair responses in fibrotic diseases. The chronic profibrotic milieu induces epigenetic imprinting in myofibroblasts, which serves as a self-amplifying loop to consolidate fibroblast activation in the later stages of fibrotic diseases.