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Fibrosis: cross-organ biology and pathways to development of innovative drugs

Abstract

Fibrosis is a pathophysiological mechanism involved in chronic and progressive diseases that results in excessive tissue scarring. Diseases associated with fibrosis include metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel diseases (IBDs), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc), which are collectively responsible for substantial morbidity and mortality. Although a few drugs with direct antifibrotic activity are approved for pulmonary fibrosis and considerable progress has been made in the understanding of mechanisms of fibrosis, translation of this knowledge into effective therapies continues to be limited and challenging. With the aim of assisting developers of novel antifibrotic drugs, this Review integrates viewpoints of biologists and physician-scientists on core pathways involved in fibrosis across organs, as well as on specific characteristics and approaches to assess therapeutic interventions for fibrotic diseases of the lung, gut, kidney, skin and liver. This discussion is used as a basis to propose strategies to improve the translation of potential antifibrotic therapies.

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Fig. 1: Initiation of fibrosis.

Fig. 2: Myofibroblast activation states and pathways.

Fig. 3: Key mechanisms involved in the development of pulmonary fibrosis.

Fig. 4: Core mechanisms of intestinal fibrogenesis.

Fig. 5: Key pathways of chronic kidney disease and fibrosis.

Fig. 6: Mechanisms of fibrotic tissue remodelling in systemic sclerosis.

Fig. 7: Key pathways of liver fibrosis progression and regression.

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Acknowledgements

The authors thank the Helmsley Charitable Trust for supporting the construction of a pathway to test antifibrotic therapies in IBD. The research of L.E.N. is funded in part by grants from NIH P50AA024333, R01AA027456, U01AA026398 and R01AA030699. B.H.’s research is supported by grants from the Canadian Institutes of Health Research CIHR (#375597, #190081) and joint support from the Canada Foundation for Innovation (CFI) and the Ontario Research Fund (ORF) (#36050, #38861, #36349). T.M.M. is supported by an NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017) British Lung Foundation Chair in Respiratory Research (C17-3).

Author information

Author notes

These authors contributed equally: Florian Rieder, Marco Prunotto.

Authors and Affiliations

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

Florian Rieder

Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA

Florian Rieder & Laura E. Nagy

Program for Global Translational Inflammatory Bowel Diseases (GRID), Chicago, IL, USA

Florian Rieder

Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA

Laura E. Nagy

Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Toby M. Maher

National Heart and Lung Institute, Imperial College, London, UK

Toby M. Maher

Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany

Jörg H. W. Distler

Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany

Jörg H. W. Distler

Department of Nephrology and Clinical Immunology, RWTH Aachen; Medical Faculty, Aachen, Germany

Rafael Kramann

Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands

Rafael Kramann

Keenan Research Institute for Biomedical Science of the St Michael’s Hospital, Toronto, Ontario, Canada

Boris Hinz

Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada

Boris Hinz

Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland

Marco Prunotto

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Florian Rieder

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