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Pulmonary fibrosis is thought to result from dysregulated wound repair after repetitive lung injury. Many cellular responses to injury involve rearrangements of the actin cytoskeleton mediated by the two isoforms of the Rho-associated coiled coil forming protein kinase, ROCK1 and ROCK2. Additionally, profibrotic mediators such as transforming growth factor-beta (TGF-β), thrombin and lysophosphatidic acid (LPA) act through receptors that activate ROCK. Inhibition of ROCK activation may be a potent therapeutic strategy for human pulmonary fibrosis. Pharmacological inhibition of ROCK using non-selective ROCK inhibitors has been shown to prevent fibrosis in animal models, however the specific roles of each ROCK isoform are poorly understood. Furthermore, the pleiotropic effects of this kinase have raised concerns about on-target adverse effects of ROCK inhibition such as hypotension. Selective inhibition of one isoform might be a better tolerated strategy. Here we utilized a genetic approach to determine the roles of ROCK1 and ROCK2 in a mouse model of bleomycin-induced pulmonary fibrosis. Using ROCK1 or ROCK2 haploinsufficient mice, we found that reduced expression of either ROCK1 or ROCK2 was sufficient to protect from bleomycin-induced pulmonary fibrosis. In addition, we found that both isoforms contribute to the pro-fibrotic responses of epithelial cells, endothelial cells and fibroblasts. Interestingly, ROCK1 and ROCK2 haploinsufficient mice exhibited similar protection from bleomycin-induced vascular leak, myofibroblast differentiation and fibrosis; however, ROCK1 haploinsufficient mice demonstrated greater attenuation of epithelial cell apoptosis. These findings suggest that selective inhibition of either ROCK isoform has the potential to be an effective therapeutic strategy for pulmonary fibrosis.
This article was published in the following journal.
Name: American journal of respiratory cell and molecular biology
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A casein kinase I isoenzyme that plays a role in intracellular signaling pathways including the CELL CYCLE, membrane trafficking, and RNA processing. In DROSOPHILA casein kinase Ialpha has been in regulation of Hedghog and Wingless signaling pathways. Multiple isoforms of casein kinase Ialpha exist and are due ALTERNATIVE SPLICING.
A 70-kDa MAP kinase kinase kinase with specificity for MAP KINASE KINASE 5. It is activated during the cellular response to GROWTH FACTORS, oxidative stress, and hyperosmotic conditions.
A 195-kDa MAP kinase kinase kinase with broad specificity for MAP KINASE KINASES. It is found localized in the CYTOSKELETON and can activate a variety of MAP kinase-dependent pathways.
A monomeric calcium-calmodulin-dependent protein kinase subtype that is expressed in a broad variety of mammalian cell types. Its expression is regulated by the action of CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE. Several isoforms of this enzyme subtype are encoded by distinct genes.
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