Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds

Nakamura, Ryosuke; Mukudai, Shigeyuki; Bing, Renjie; Garabedian, Michael J.; Branski, Ryan C.

doi:10.1038/s41598-020-77445-9

Cited by 10 publications

(20 citation statements)

References 38 publications

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“…However, we did not find a difference in baseline lung function and administration of steroids. In vitro steroids have mixed effects on fibroblast function and contradictory profibrotic and anti-fibrotic effect of steroids on fibroblasts are reported [36,37]. There are some clinical studies that evaluated the impact of steroids on CTD-ILD.…”

Section: Discussionmentioning

confidence: 99%

Predictors for progressive fibrosis in patients with connective tissue disease associated interstitial lung diseases

Chiu

Spierings

Jong

et al. 2021

Respiratory Medicine

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Section: Discussionmentioning

confidence: 99%

Predictors for progressive fibrosis in patients with connective tissue disease associated interstitial lung diseases

Chiu

Spierings

Jong

et al. 2021

Respiratory Medicine

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“…6,15 In addition, our recent work suggested both anti-and pro-fibrotic responses in a single cell type. 15 The inherent complexity of GCs and cell-level responses, putatively, are the source of variability in clinical outcomes for fibrosis of the vocal folds. 6 Broadly, we hypothesize that optimization of GC therapy will substantively improve clinical outcomes.…”

Section: Introductionmentioning

confidence: 97%

“…We recently reported increased dexamethasone concentrations were required to synergistically enhance the fibrotic effects of transforming growth factor-β (TGF-β) relative to inhibition of inflammatory genes in human VF fibroblasts. 15 Dose-dependent differential effects of GCs have also been reported in neuronal cells. 22 Beyond these preliminary data, little information exists to direct optimal clinical care paradigms involving GCs.…”

Section: Introductionmentioning

confidence: 97%

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Glucocorticoid Dose Dependency on Gene Expression in Vocal Fold Fibroblasts and Macrophages

et al. 2022

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Objective Glucocorticoids (GCs) modulate multiple cellular activities including inflammatory and fibrotic responses. Outcomes of GC treatment for laryngeal disease vary, affording opportunity to optimize treatment. In the current study, three clinically employed GCs were evaluated to identify optimal in vitro concentrations at which GCs mediate favorable anti‐inflammatory and fibrotic effects in multiple cell types. We hypothesize a therapeutic window will emerge as a foundation for optimized therapeutic strategies for patients with laryngeal disease. Study Design In vitro. Methods Human vocal fold fibroblasts and human macrophages derived from THP‐1 monocytes were treated with 0.03–1000 nM dexamethasone, 0.3–10,000 nM methylprednisolone, and 0.3–10,000 nM triamcinolone in combination with interferon‐γ, tumor necrosis factor‐α, or interleukin‐4. Real‐time polymerase chain reaction was performed to analyze inflammatory (CXCL10, CXCl11, PTGS2, TNF, IL1B) and fibrotic (CCN2, LOX, TGM2) genes, and TSC22D3, a target gene of GC signaling. EC50 and IC50 to alter inflammatory and fibrotic gene expression was calculated. Results Interferon‐γ and tumor necrosis factor‐α increased inflammatory gene expression in both cell types; this response was reduced by GCs. Interleukin‐4 increased LOX and TGM2 expression in macrophages; this response was also reduced by GCs. GCs induced TSC22D3 and CCN2 expression independent of cytokine treatment. EC50 for each GC to upregulate CCN2 was higher than the IC50 to downregulate other genes. Conclusion Lower concentrations of GCs repressed inflammatory gene expression and only moderately induced genes involved in fibrosis. These data warrant consideration as a foundation for optimized clinical care paradigms to reduce inflammation and mitigate fibrosis. Level of Evidence NA Laryngoscope, 133:1169–1175, 2023

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“…Fibroblasts are key to extracellular matrix metabolism and in vitro investigation of tissue-specific fibroblasts from the vocal folds are fundamental to our understanding of this specialized connective tissue, and more importantly, the development of novel therapeutics. Relevant to the current investigation, glucocorticoids are ubiquitously employed in the upper airway and are known regulators of multiple processes in VFF fibroblasts [18, 19]. As such, we hypothesized that, at baseline, fibroblasts from the vocal folds will be colonized with mycoplasma, and furthermore, this colonization will significantly alter both baseline genetic profiles as well as the inherent response to exogenous glucocorticoids.…”

Section: Introductionmentioning

confidence: 99%

Mycoplasma affects baseline gene expression and the response to glucocorticoids in vocal fold fibroblasts

Doyle

Nakamura

Bing

et al. 2021

Journal of Medical Microbiology

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Introduction. In vitro experimentation is intentionally contrived to isolate specific phenomena in the context of profound biological complexity. Mycoplasmas in the upper airway likely contribute to this complexity and play a largely unknown role in both health and disease. Similarly, the presence and role of mycoplasma in in vitro investigation are largely unknown. Hypothesis. We hypothesize mycoplasma in human vocal fold fibroblasts (VFF) will affect both basal gene-expression patterns as well as the cell response to exogenous stimuli. Aim. We sought to determine mycoplasma presence across vocal fold fibroblast cultures, basal transcriptional changes as a function of mycoplasma, and responsiveness to exogenous glucocorticoids in mycoplasma-positive and -negative VFF. Methodology. PCR-based mycoplasma detection was performed in an immortalized human VFF line as well as rat and rabbit primary VFF cultures and extracted rat laryngeal tissue. RNA sequencing was performed in mycoplasma-positive and -negative human cells at baseline and in response to dexamethasone. Results. Mycoplasma was identified in the human cell line as well as primary culture from rabbits. Mycoplasma was not detected in tissue or primary culture from rat vocal folds. Basal mRNA expression in human VFF differed significantly following mycoplasma treatment. In addition, differential responses to dexamethasone were observed across multiple pathways as a function of mycoplasma presence in these cells. Pathways including apoptosis, DNA damage repair, and G1 to S cell cycle signalling were significantly enriched in mycoplasma-positive cells. Conclusion. Variability of mycoplasma presence across culture conditions and differential responses to exogenous stimuli as a function of mycoplasma presence are potentially problematic for the translation of in vitro experimentation in the upper aerodigestive tract. It remains unclear if these findings represent contamination or the baseline state of this specialized tissue.

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Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds

Cited by 10 publications

References 38 publications

Predictors for progressive fibrosis in patients with connective tissue disease associated interstitial lung diseases

Predictors for progressive fibrosis in patients with connective tissue disease associated interstitial lung diseases

Glucocorticoid Dose Dependency on Gene Expression in Vocal Fold Fibroblasts and Macrophages

Mycoplasma affects baseline gene expression and the response to glucocorticoids in vocal fold fibroblasts

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