Figure 1. Myofibroblast dynamics. Lung fibroblasts undergo actin cytoskeleton and actomyosin contractile system remodeling in response to biomechanical and biochemical stimuli. This remodeling leads to enhanced fibroblast contraction, which results in the translocation of myocardin-related transcription factor A (MKL1; MAL; MRTF-A) from the cytoplasm to the nucleus. The result is activation of fibrotic genes that induce myofibroblast differentiation, such as actin a2 smooth aorta muscle (ACTA2; a-SMA) and collagen type I a2 (COL1A2).

The Alabama team showed that the Rho kinase inhibitor fasudil disrupts the actin cytoskeleton required for myofibroblast contractility in pre-existing myofibroblasts. This deactivates a constitutively activated MKL1 nuclear signal in myofibroblasts, resulting in blockade of fibroblast-to-myofibroblast differentiation and downregulation of the antiapoptotic protein B cell lymphoma 2 (BCL-2; BCL2) to activate apoptosis.

Rho kinase inhibitors could provide additive or synergistic anti­fibrotic effects with inhibitors of transforming growth factor-b1 (TGFB1)
such as Esbriet pirfenidone. (Figure based on Figure 7 in ref. 1.)