The effects of cytosporone‐B, a novel antifibrotic agent, on vocal fold fibroblasts

Abstract

Objectives/Hypothesis Our laboratory recently described NR4A1 as an endogenous inhibitor of TGF-β-induced vocal fold (VF) fibrosis. Our prior report described the temporal expression of NR4A1 during VF healing in vivo and the effects of NR4A1 knockdown on fibroplastic cell activities in vitro. Based on these findings, we hypothesized that Cytosporone-B (Csn-B), a NR4A1 agonist, may hold significant therapeutic potential. Study Design In vitro. Methods Human VF fibroblasts were exposed to TGF-β1+/-Csn-B. Expression of genes related to fibrosis were quantified. In addition, contraction was assayed as a surrogate for the fibrotic phenotype in our cell line. Results TGF-B1 stimulated COL1A1 and ACTA2, as expected. Csn-B significantly downregulated TGF-β1-mediated upregulation of these genes (p=0.009, p=0.03, respectively). Csn-B had no effect on genes related to TGF-β/Smad signaling. Csn-B also decreased the TGF-β1-mediated contractile phenotype in our cells (p=0.004). Conclusions NR4A1 is an endogenous inhibitor of fibrosis in the vocal folds and Csn-B, as an NR4A1 agonist, may evolve as an ideal, therapeutic candidate for this challenging condition. Level of Evidence N/A

The Role of Cytokines in Modulating Vocal Fold Fibrosis: A Contemporary Review

“…31 Specifically, Smad3 is considered a master regulator of fibrosis. 32 Molecular signaling offers a new strategy to intervene in scar formation. Specific siRNA-mediated Smad knockdown can decrease the expression of targeted genes and attenuate profibrotic cell activities induced by TGF-β stimulation, providing a therapeutic target to reverse the profibrotic phenotype.…”

Pathophysiology of Fibrosis in the Vocal Fold: Current Research, Future Treatment Strategies, and Obstacles to Restoring Vocal Fold Pliability

“…Hiwatashi et al described orphan nuclear receptor 4A1 (NR4A1) is an endogenous inhibitor of TGF-β-induced VF fibrosis. Therefore, cytosporone-B, as an NR4A1 agonist, may be a new therapeutic candidate for VF scar [111]. Another candidate of antifibrotic agent for VF scars, Halofuginone, an inhibitor of the TGF-β fibrotic cascade selectively inhibits smad-3 activation of pro-collagen mRNA transcription.…”

Phlorotannins ameliorate extracellular matrix production in human vocal fold fibroblasts and prevent vocal fold fibrosis via aerosol inhalation in a laser‐induced fibrosis model

“…Fibrosis is an irregularity resulting from the overaccumulation of the extracellular matrix (ECM) that can occur in various tissues and organs, such as the heart, liver, lung, skin, and vocal folds (VFs). It is typically accompanied by the excessive deposition of collagen (COL), the disorganization of elastin, and a reduction in hyaluronic acid (Hiwatashi, Mukudai, Bing, & Branski, 2018; Jun & Lau, 2018). It is mainly caused by abnormal wound healing processes after tissue and/or organ damage (Yoon, Kang, & Eom, 2019).…”