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Mar 21, 2013
 |  BC Innovations  |  Targets & Mechanisms

Understanding fibrosis

Researchers at The University of Alabama at Birmingham have identified idiopathic pulmonary fibrosis as a repurposing opportunity for fasudil, a Rho kinase inhibitor that Asahi Kasei Pharma Corp. markets as Eril to treat aneurysm. The key observation was that the drug acts on a pathway that converts biochemical or biomechanical stimuli into fibrogenic signals that sustain myofibroblast activation and survival.1

The team now needs to develop a formulation of fasudil or other Rho kinase inhibitors that works only in the lung and thus avoids systemic side effects.

In normal wound healing, fibroblasts that reside in tissues are activated and transform into myofibroblasts, which are characterized by high contractile activity that results from actin a2 smooth aorta muscle (ACTA2; a-SMA) accumulation in stress fibers. The myofibroblasts help remodel and repair tissue by secreting extracellular matrix components, such as collagen and fibronectin.

Once the wound is re-epithelialized, the myofibroblasts undergo apoptosis.2

In fibrotic disease, apoptotic-resistant myofibroblasts persist in injured tissues and can lead to excessive accumulation of fibrous connective tissue and tissue stiffening. This accumulation can result in permanent scarring, organ malfunction and possibly death, as seen in end-stage idiopathic pulmonary fibrosis (IPF).

Fibrogenic cytokines and growth factors, such as transforming growth factor-b1 (TGFB1), are known promoters of fibroblast-to-myofibroblast differentiation, but the Alabama team has been searching for other contributors.

In 2012, the group showed that biomechanical properties of the extracellular matrix contribute to differentiation. The researchers reported that mouse lung fibroblasts cultured on a stiff matrix showed greater actin cytoskeletal reorganization and myofibroblast differentiation than those cultured on soft matrix.3

However, inhibiting Rho kinase activity prevented those changes. Rho kinases-including Rho-associated coiled-coil containing protein kinase 1 (ROCK1) and ROCK2-are involved in regulating cell contractility, actin cytoskeletal organization, stress fiber formation and focal adhesion assembly.

Now, the team has probed the underpinnings of the pathway that converts...

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