Mechanisms Underlying the Antifibrotic Potential of Estradiol for Vocal Fold Fibrosis

Abstract

Objectives/Hypothesis: Vocal fold fibrosis remains a significant clinical challenge. Estrogens, steroid hormones predominantly responsible for secondary sexual characteristics in women, have been shown to alter wound healing and limit fibrosis, but the effects on vocal fold fibrosis are unknown. We sought to elucidate the expression of estrogen receptors and the effects of estrogens on TGF-β1 signaling in rat vocal fold fibroblasts (VFFs).Study Design: In vitro. Methods: VFFs were isolated from 10-week-old, male Sprague-Dawley rats, and estrogen receptor alpha (ERα) and G protein-coupled receptor 30 (GPR30) were examined via immunostaining and quantitative polymerase chain reaction (qPCR). VFFs were treated with estradiol (E2, 10 −7 , 10 −8 or 10 −9 M) AE transforming growth factor beta 1 (TGF-β1, 10 ng/mL). ICI 182,780 (ICI, 10 −7 M) or G36 (10 −7 M) were employed as antagonists of ERα or GPR30, respectively. qPCR was employed to determine estrogen receptor-mediated effects of E2 on genes related to fibrosis.Results: ERα and GPR30 were expressed in VFFs at both the protein and the mRNA levels. E2 (10 −7 M) did not alter Smad3, Smad7, Acta2 mRNA, or extracellular matrix related genes. However, the combination of E2 (10 −8 M) and TGF-β1 significantly increased Smad7 (P = .03) and decreased Col1a1 (P = .04) compared to TGF-β1 alone; this response was negated by the combination of ICI and G36 (P = .009).Conclusions: E2 regulated TGF-β1/Smad signaling via estrogen receptors in VFFs. These findings provide insight into potential mechanisms of estrogens on vocal fold injury with the goal of enhanced therapeutics for vocal fold fibrosis.

The Effect of Melatonin on Nasal Septal Wound Healing in an Experimental Animal Model

“…The sex hormones affect wound healing. 21,22 Therefore, only male animals were included in this study to exclude hormonal effects. The perforations were performed with a cannula to standardize the NSPs.…”

“…We planned this experimental study to investigate the effects of MLT on NSP healing. The sex hormones affect wound healing (21,22). Therefore, only male animals were included in this study to exclude hormonal effects.…”

The effect of hypertonic alkaline nasal irrigation on nasal wound healing in an experimental animal model

“…[15,17,18] There are differences between the sexes, mainly due to hormonal effects, particularly estrogen, on wound healing. [19] Therefore, only male rats participated in the present study. In our study, we planned to examine the healing parameters of a wound belonging to the nasal septum as it is the formation containing the most different types of tissue in the nasal cavity.…”

“…Van Lake-based hypertonic alkaline nasal irrigation (HANI) solution is a hypertonic alkaline solution that contains 12 g/L of NaCl, 1.1 g/L of magnesium sulfate heptahydrate (MgSO 4 .7H 2 O), 0.1 g/L of calcium chloride dihydrate (CaCl 2 .2H 2 O), 0.8 g/L of potassium chloride (KCl), 4 g/L of sodium bicarbonate (NaHCO 3 ), and 2 g/L of sodium sulfate (Na 2 SO 4 ), and its pH is 9. In a clinical study, it has been shown that HANI reduces the nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) load and alleviates the clinic associated with coronavirus disease 2019 (COVID- 19). [1,2] The wound is the disruption of the normal functional anatomy of the tissues due to internal or external causes.…”

Scarless Healing of Injured Vocal Folds Using an Injectable Hyaluronic Acid-Waterborne Polyurethane Hybrid Hydrogel to Tune Inflammation and Collagen Deposition

“…7 Treatment of scarred VF includes voice therapy, scar excision, localized steroid injection, and biomaterial injection or implantation. 8 Although voice therapy is non-invasive, the duration is usually long and requires the cooperation of patients. Meanwhile, the improvements are not ideal.…”