The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis
Open accessAbstract
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring, short median survival, and limited therapeutic options, creating great need for new pharmacologic therapies. IPF is thought to result from repetitive environmental injury to the lung epithelium, in the context of aberrant host wound healing responses. Tissue responses to injury fundamentally involve reorganization of the actin cytoskeleton of participating cells, including epithelial cells, fibroblasts, endothelial cells, and macrophages. Actin filament assembly and actomyosin contraction are directed by the Rho-associated coiled-coil forming protein kinase (ROCK) family of serine/threonine kinases (ROCK1 and ROCK2). As would therefore be expected, lung ROCK activation has been demonstrated in humans with IPF and in animal models of this disease. ROCK inhibitors can prevent fibrosis in these models, and more importantly, induce the regression of already established fibrosis. Here we review ROCK structure and function, upstream activators and downstream targets of ROCKs in pulmonary fibrosis, contributions of ROCKs to profibrotic cellular responses to lung injury, ROCK inhibitors and their efficacy in animal models of pulmonary fibrosis, and potential toxicities of ROCK inhibitors in humans, as well as involvement of ROCKs in fibrosis in other organs. As we discuss, ROCK activation is required for multiple profibrotic responses, in the lung and multiple other organs, suggesting ROCK participation in fundamental pathways that contribute to the pathogenesis of a broad array of fibrotic diseases. Multiple lines of evidence therefore indicate that ROCK inhibition has great potential to be a powerful therapeutic tool in the treatment of fibrosis, both in the lung and beyond.
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A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats
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Allen, R. J., Porte, J., Braybrooke, R., Flores, C., Fingerlin, T. E., Oldham, J. M., Guillen-Guio, B., Ma, S.-F., Okamoto, T., John, A. E., et al. (2017) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(17)30387-9 · Cited by 297 · see citing works
Idiopathic pulmonary fibrosis.
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Li, Q., Cheng, Y., Zhang, Z., Bi, Z., Ma, X., Wei, Y., & Wei, X. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.1036 · Cited by 77 · see citing works
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Modelling and targeting mechanical forces in organ fibrosis
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Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies
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Liu, L., Song, W., Zeng, J., & Peng, Z. (2022) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.2c00149 · Cited by 8 · see citing works
- Authors
- Knipe, R. S., Tager, A. M., & Liao, J. K.
- Affiliations
- Harvard University (US)
- Venue
- Pharmacological Reviews
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 67
- Issue
- 1
- Pages
- 103-117
- ISSN
- 0031-6997 (ISSN-L)
- PMC
- PMC4279074
- OpenAlex
- W2155116729
- Cited by
- 233
- References
- 150
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 24 · 2023: 25 · 2022: 19 · 2021: 28 · 2020: 21 · 2019: 13 · 2018: 20 · 2017: 21 · 2016: 14 · 2015: 4
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Pharmacological Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Scleroderma Research Foundation
- National Institutes of Health (UL1TR000430)
- National Heart, Lung, and Blood Institute (HL095732, HL-108975, HL-052233, R01HL095732, R01HL091933, R01HL108975, R01HL052233, T32HL116275)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK085006)
- National Institute of Neurological Disorders and Stroke (R01NS070001)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR007258)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Rho kinase, ROCK1, ROCK2, idiopathic pulmonary fibrosis, pulmonary fibrosis, ROCK inhibitor, profibrotic signaling, actin cytoskeleton, lung injury, wound healing, fibrosis regression, fibrotic diseases
- MeSH terms
- Animals, Disease Models, Animal, Humans, Lung, Protein Conformation, Structure-Activity Relationship, Drug Design, Signal Transduction, Protein Kinase Inhibitors, rho-Associated Kinases, Idiopathic Pulmonary Fibrosis, Molecular Targeted Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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