Effects of Repeated Intracordal Glucocorticoid Injection on the Histology and Gene Expression of Rat Vocal Folds

Hashimoto, Keiko; Kaneko, Mitsuaki; Kinoshita, Shingo; Ozawa, Satomi; Mukudai, Shigeyuki; Sugiyama, Yoichiro; Hirano, Shigeru

doi:10.1016/j.jvoice.2021.06.013

Cited by 4 publications

(7 citation statements)

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“…5 For example, triamcinolone acetonide injection had a relatively unclear therapeutic effect on vocal scar, 6 compared to dexamethasone. 7 Risks of GC injection on muscular and mucosal atrophy have also been reported, 8,9 and more recent data suggest a pro-fibrotic response to GCs in the larynx. 10 In that regard, GCs have divergent effects on fibrosis across organs [11][12][13][14] In vitro data from our group confirmed both anti-and pro-fibrotic effects of GCs in human vocal fold (VF) fibroblasts and macrophages.…”

Section: Introductionmentioning

confidence: 98%

Dose‐Dependent Glucocorticoid Regulation of Transcription Factors in Vocal Fold Fibroblasts and Macrophages

et al. 2023

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ObjectiveVariable outcomes of glucocorticoid (GC) therapy for laryngeal disease are putatively due to diverse interactions of the GC receptor (GR) with cell signaling pathways, limited consideration regarding concentration‐dependent effects, and inconsistent selection of GCs. In the current study, we evaluated the concentration‐dependent effects of three frequently administered GCs on transcription factors with an emphasis on the phosphorylation of GR at Ser203 and Ser211 regulating the nuclear translocation of GR. This study provides foundational data regarding the diverse functions of GCs to optimize therapeutic approaches.Study designIn vitro.MethodsHuman vocal fold fibroblasts and THP1‐derived macrophages were treated with different concentrations of dexamethasone, methylprednisolone, and triamcinolone in combination with IFN‐γ, TNF‐α, or IL4. Phosphorylated STAT1, NF‐κB family molecules, and phosphorylated STAT6 were analyzed by Western blotting. Ser211‐phosphorylated GR (S211‐pGR) levels relative to GAPDH and Ser203‐phosphorylated GR (S203‐pGR) were also analyzed.ResultsGCs differentially altered phosphorylated STAT1 and NF‐κB family molecules in different cell types under IFN‐γ and TNF‐α stimuli. GCs did not alter phosphorylated STAT6 in IL4‐treated macrophages. The three GCs were nearly equivalent. A lower concentration of dexamethasone increased S211‐pGR/GAPDH ratios relative to increased S211‐pGR/S203‐pGR ratios regardless of cell type and treatment.ConclusionThe three GCs employed in two cell lines had nearly equivalent effects on transcription factor regulation. Relatively high levels of Ser203‐phosphorylation at low GC concentrations may be related to concentration‐dependent differential effects of GCs in the two cell lines.Level of EvidenceNA Laryngoscope, 133:2704–2711, 2023

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Section: Introductionmentioning

confidence: 98%

Dose‐Dependent Glucocorticoid Regulation of Transcription Factors in Vocal Fold Fibroblasts and Macrophages

et al. 2023

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“…Only a small subset of studies utilizing intracordal injections address GC induced atrophy in VF tissue, with little attention to the specific mechanism(s) involved, mucosa/muscle specificity, or dose and GC specificity. 41,43,44 Increased TA muscle fiber CSA may be related to VF tissue specificity and/or influence of variables associated with systemic injections. However, these mechanistic hypotheses are speculative and require further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…In that regard, "atrophy" in this study was defined as only a muscular finding, but atrophy is a multi-modal phenomenal observed to effect the VF lamina propria and epithelium. 41,42 Additionally, GCs are typically administered for laryngeal indications that frequently involve an inflammatory response in the VFs or surrounding tissue. It is reasonable to believe that this inflammatory response, characterized by an influx of immune cells, the release of inflammatory mediators, and chemoattraction of other cell types, influences how GCs interact with the VF tissue.…”

Section: Discussionmentioning

confidence: 99%

Acute Effects of Systemic Glucocorticoids on the Vocal Folds in a Pre-Clinical Model

Gartling

Nakamura

Sayce

et al. 2023

Ann Otol Rhinol Laryngol

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Objectives/Hypothesis: Systemic glucocorticoids (GC)s are employed to treat various voice disorders. However, GCs have varying pharmacodynamic properties with adverse effects ranging from changes in epithelial integrity, skeletal muscle catabolism, and altered body weight. We sought to characterize the acute temporal effects of systemic dexamethasone and methylprednisolone on vocal fold (VF) epithelial glucocorticoid receptor (GR) nuclear translocation, epithelial tight junction (ZO-1) expression, thyroarytenoid (TA) muscle fiber morphology, and body weight using an established pre-clinical model. We hypothesized dexamethasone and methylprednisolone will elicit changes in VF epithelial GR nuclear translocation, epithelial ZO-1 expression, TA muscle morphology, and body weight compared to placebo-treated controls. Methods: Forty-five New Zealand white rabbits received intramuscular injections of methylprednisolone (4.5 mg; n = 15), dexamethasone (450 µg; n = 15), or volume matched saline ( n = 15) into the iliocostalis/longissimus muscle for 6 consecutive days. Vocal folds from 5 rabbits from each treatment group were harvested at 1-, 3-, or 7 days following the final injection and subjected to immunohistochemistry for ZO-1 and GR as well as TA muscle fiber cross-sectional area (CSA) measures. Results: Dexamethasone increased epithelial GR nuclear translocation and ZO-1 expression 1-day following injections compared to methylprednisolone ( P = .024; P = .012). Dexamethasone and methylprednisolone increased TA CSA 1-day following injections ( P = .011). Methylprednisolone decreased body weight 7 days following injections compared to controls ( P = .004). Conclusions: Systemic dexamethasone may more efficiently activate GR in the VF epithelium with a lower risk of body weight loss, suggesting a role for more refined approaches to GC selection for laryngeal pathology.

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“…In animal models, a single intracordal triamcinolone injection in rabbits decreased thyroarytenoid (TA) muscle fiber size 4‐weeks following treatment 14 . A single intracordal triamcinolone injection in rats suppressed genes associated with hyaluronic acid synthesis 1‐ and 3‐days post‐treatment 15 . Additionally, four weekly triamcinolone injections in rats decreased hyaluronic acid concentration in the VF lamina propria 15 .…”

Section: Introductionmentioning

confidence: 99%

“…A single intracordal triamcinolone injection in rats suppressed genes associated with hyaluronic acid synthesis 1‐ and 3‐days post‐treatment 15 . Additionally, four weekly triamcinolone injections in rats decreased hyaluronic acid concentration in the VF lamina propria 15 . Mechanisms underlying atrophy in response to GCs have been investigated in other tissues and provide a foundation for investigation in the VFs, and ultimately, optimization of clinical paradigms.…”

Section: Introductionmentioning

confidence: 99%

Acute In Vitro and In Vivo Effects of Dexamethasone in the Vocal Folds: a Pilot Study

et al. 2022

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Objectives/HypothesisGlucocorticoids (GC)s are commonly employed to treat vocal fold (VF) pathologies. However, VF atrophy has been associated with intracordal GC injections. Dexamethasone‐induced skeletal muscle atrophy is well‐documented in other tissues and believed to be mediated by increased muscle proteolysis via upregulation of Muscle Ring Finger (MuRF)‐1 and Atrogin‐1. Mechanisms of dexamethasone‐mediated VF atrophy have not been described. This pilot study employed in vitro and in vivo models to investigate the effects of dexamethasone on VF epithelium, thyroarytenoid (TA) muscle, and TA‐derived myoblasts. We hypothesized that dexamethasone will increase atrophy‐associated gene expression in TA muscle and myoblasts and decrease TA muscle fiber size and epithelial thickness.Study DesignIn vitro, pre‐clinical.MethodsTA myoblasts were isolated from a female Sprague–Dawley rat and treated with 1 μM dexamethasone for 24‐h. In vivo, 15 New Zealand white rabbits were randomly assigned to three treatment groups: (1) bilateral intracordal injection of 40 μL dexamethasone (10 mg/ml; n = 5), (2) volume‐matched saline (n = 5), and (3) untreated controls (n = 5). Larynges were harvested 7‐days post‐injection. Across in vivo and in vitro experimentation, MuRF‐1 and Atrogin‐1 mRNA expression were measured via RT‐qPCR. TA muscle fiber cross‐sectional area (CSA) and epithelial thickness were also quantified in vivo.ResultsDexamethasone increased MuRF‐1 gene expression in TA myoblasts. Dexamethasone injection, however, did not alter atrophy‐associated gene expression, TA CSA, or epithelial thickness in vivo.ConclusionDexamethasone increased atrogene expression in TA myoblasts, providing foundational insight into GC induced atrophic gene transcription. Repeated dexamethasone injections may be required to elicit atrophy in vivo.Level of EvidenceNA Laryngoscope, 133:2264–2270, 2023

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Effects of Repeated Intracordal Glucocorticoid Injection on the Histology and Gene Expression of Rat Vocal Folds

Cited by 4 publications

References 14 publications

Dose‐Dependent Glucocorticoid Regulation of Transcription Factors in Vocal Fold Fibroblasts and Macrophages

Dose‐Dependent Glucocorticoid Regulation of Transcription Factors in Vocal Fold Fibroblasts and Macrophages

Acute Effects of Systemic Glucocorticoids on the Vocal Folds in a Pre-Clinical Model

Acute In Vitro and In Vivo Effects of Dexamethasone in the Vocal Folds: a Pilot Study

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