Reversal of myofibroblast differentiation: A review

Mechanisms of Lung Fibrosis Resolution

“…64 Nuclear factor erythroid 2-related factor 2 (NRF2) is regarded as a master regulator of cellular resistance to oxidants and regulates expression of genes, limiting the inflammatory and fibrotic responses. 39 In primary IPF and normal lung fibroblasts, siRNA activation of NRF2 by either Keap1 siRNA or sulforaphane induced myofibroblast dedifferentiation with down-regulation of a-SMA, along with reduced cell proliferation, migration, and contraction, and was associated with restored oxidant/antioxidant balance in the cells. 52 NRF2 knockdown abolished Suforaphane's dedifferentiation effects, suggesting that they were NRF2 mediated.…”

“…58 Prostaglandin E2 (PGE2) is an endogenously produced lipid mediator that inhibits multiple fibroblast functions, including proliferation, collagen production, and differentiation. 39 In fetal and adult lung fibroblasts, the addition of PGE2 reversed TGF-b1 and endothelin-1einduced myofibroblast differentiation via inhibition of focal adhesion kinase activation. 54 This effect was not explained by apoptosis, and reintroduction of TGF-b1 2 days after the addition of PGE2 prompted dedifferentiated fibroblasts to reexpress a-SMA, indicating redifferentiation to myofibroblasts.…”

“…39,40 Myofibroblasts are essential in normal wound healing by facilitating wound closure and synthesis of ECM proteins. 3 Termination of the reparative response that leads to normal wound healing includes the elimination of myofibroblasts from granulation tissue.…”

“…In contrast, the persistence of myofibroblasts in injured tissues is associated with nonresolving and progressive fibrosis in the lung and other organs. 39,41 Because myofibroblasts are the main effectors of fibrosis, successful resolution is dependent on inhibiting myofibroblast differentiation from precursor cells and eliminating active myofibroblasts. Myofibroblast differentiation is triggered by several mediators, including cytokines, growth factors, and ECM composition, as recently reviewed.…”

“…Myofibroblast differentiation is triggered by several mediators, including cytokines, growth factors, and ECM composition, as recently reviewed. 39 However, even if differentiation can be inhibited, persistent myofibroblasts can induce a feedforward mechanism for maintaining the myofibroblast phenotype and inducing neighboring cells into fibrotic and dysfunctional cells through mechanotransductionmediated up-regulation of profibrotic and prosurvival genes. 39,41,42 Therefore, elimination of embedded myofibroblasts is paramount to promoting resolution.…”