Abstract
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.
Key points
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In fibrotic diseases, disease-specific triggers initiate site-specific injuries, which activate distinct cells that drive fibrosis in a genetically susceptible individual.
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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.
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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.
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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.
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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.
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Acknowledgements
The authors’ research is supported by the grants DI 1537/7-1, DI 1537/8-1, DI 1537/9-1 DI 153/9-2, DI 1537/11-1, DI 1537/12-1, DI 1537/13-1 and DI 1537/14-1 of the German Research Foundation, SFB CRC1181 (project C01) and SFB TR221/ project number 324392634 (B04) of the German Research Foundation and a Career Support Award of Medicine of the Ernst Jung Foundation.
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J.H.W.D. declares that he has consultancy relationships and/or has received research funding from Actelion, Active Biotech, Array Biopharma, Bayer Pharma, Boehringer Ingelheim, BMS, Celgene, GSK, JB Therapeutics, Novartis, Sanofi-Aventis and UCB in the area of potential treatments for systemic sclerosis, and owns stock in 4D Science GmbH. M.R. declares that she is an employee of Boehringer-Ingelheim. The other authors declare no competing interests.
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Glossary
- Epigenetic modifications
-
Heritable differences in gene expression that are not encoded by changes of the nucleotide sequence.
- Mitogens
-
Chemical substances that induce cell division.
- Mesangial cells
-
Specialized cells that form the renal mesangium.
- Senolytic therapies
-
Drugs that selectively induce the death of senescent cells.
- Mitophagy
-
The selective removal of mitochondria by autophagy.
- CpG islands
-
Regions of DNA with a high frequency of cytosine–guanine dinucleotides.
- Antagomirs
-
Chemically modified oligonucleotides that are used to silence microRNAs by binding specifically to particular microRNAs.
- Keratoacanthomas
-
Benign tumours of the skin, originating from the hair follicle.
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Distler, J.H.W., Györfi, AH., Ramanujam, M. et al. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol 15, 705–730 (2019). https://doi.org/10.1038/s41584-019-0322-7
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DOI: https://doi.org/10.1038/s41584-019-0322-7
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