Control of lung myofibroblast transformation by monovalent ion transporters

Abstract Myofibroblast differentiation is a critical process in the pathogenesis of tissue fibrosis. We focus our mini-review on recent data showing an implication of monovalent ion transporters in fibroblast to myofibroblast transformation of human lung fibroblasts (HLF). In cultured HLF, cardiotonic steroids (CTS) known as potent inhibitors of Na + ,K + -ATPase suppress myofibroblast differentiation in parallel with up- and down-regulated expression of cyclooxygenase-2 (COX-2) and TGF-β receptor subunit TGFBR2, respectively. K + -free medium mimics antifibrotic action of CTS indicating a key role of elevated intracellular [Na + ] i /[K + ] i ratio. Augmented expression of COX-2 is abolished by inhibition of Na + /Ca 2 + exchanger. Side-by-side with CTS acting via elevation of the [Na + ] i /[K + ] i ratio fibroblast to myofibroblast transformation is also suppressed by potent inhibitors of Ca 2 + -activated chloride channels tannic acid and K + ,Cl − cotransporter DIOA. The relative impact of Ca 2 + i -mediated and -independent signaling triggered by elevated [Na + ] i /[K + ] i ratio and altered intracellular anion handling in transcriptomic changes involved in myofibroblast differentiation should be examined further.