Role of Erythromycin-Regulated Histone Deacetylase-2 in Benign Tracheal Stenosis

Huang, Zhenjie; Wei, Peng; Gan, Luoman; Zeng, Tonghua; Qin, Caicheng; Liu, Guangnan

doi:10.1155/2020/4213807

Cited by 11 publications

(13 citation statements)

References 36 publications

(33 reference statements)

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“…Tracheal stenosis (TS) is an uncommon disease caused by repeated injury and repair of the tracheal mucosa and hyperplasia of the resultant granulation tissue. 1 TS is a chronic inflammatory process that can result from several possible etiologies, where the most common being long-term mechanical ventilation with endotracheal intubation. Myriad additional etiologies can also result in luminal compromise of the proximal airway including neck trauma, tracheotomy, infection (i.e.…”

Section: Introductionmentioning

confidence: 99%

Antifibrotic Role of Nintedanib in Tracheal Stenosis After a Tracheal Wound

Fan

Fang

et al. 2021

The Laryngoscope

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Objectives/Hypothesis Tracheal stenosis is an obstructive disease of the upper airway that commonly develops as a result of abnormal wound healing. We evaluated the anti‐inflammatory and antifibrotic properties of nintedanib on tracheal stenosis both in vitro and in vivo. Study Design Prospective controlled animal study and in vitro comparative study of human cells. Methods An animal model of tracheal stenosis was induced via tracheal trauma. Postsurgical rats were orally administered with nintedanib (10 or 20 mg/kg/d) or saline (negative control) for 2 weeks, and tracheal specimens were harvested after 3 weeks. Degree of stenosis, collagen deposition, fibrotic surrogate markers expression, and T‐lymphocytic infiltration were evaluated. Human fetal lung fibroblast‐1 (HFL‐1) cells were cultured to determine the effects of nintedanib on changes of cellular biological function induced by transforming growth factor‐β1 (TGF‐β1). Results Rat tracheal stenotic tissues exhibited thickened lamina propria with irregular epithelium, characterized by significantly increased collagen deposition and elevated TGF‐β1, collagen I, α‐SMA and fibronectin expressions. Nintedanib markedly attenuated the tracheal stenotic lesions, reduced the collagen deposition and the expression of fibrotic marker proteins, and mitigated CD4+ T‐lymphocyte infiltration. Additionally, cellular proliferation and migration were decreased dose‐dependently in TGF‐β1‐stimulated HFL‐1 cells when treated with nintedanib. Furthermore, nintedanib inhibited TGF‐β1‐induced HFL‐1 differentiation and reduced the mRNA levels of the profibrotic genes. TGF‐β1‐activated phosphorylation of the TGF‐β/Smad2/3 and ERK1/2 pathways were also blocked by nintedanib. Conclusion Nintedanib effectively prevented tracheal stenosis in rats by inhibiting fibrosis and inflammation. The antifibrotic effect of nintedanib may be achieved by inhibiting fibroblasts' proliferation, migration and differentiation and suppressing the TGF‐β1/Smad2/3 and ERK1/2 signaling pathways. Level of Evidence NA Laryngoscope, 131:E2496–E2505, 2021

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Section: Introductionmentioning

confidence: 99%

Antifibrotic Role of Nintedanib in Tracheal Stenosis After a Tracheal Wound

Fan

Fang

et al. 2021

The Laryngoscope

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“…Recent studies have found that tracheal transplantation has been considered a viable option for the reconstruction of long tracheal defects, 9 while tissue engineering tracheal graft implantation may be the last chance for patients with severe cicatricial stenosis 8 . At the same time, local and systemic anti‐infection has also been found to be effective for TS, but most of the data are related to animal models 42–44 . The specific indicators of the clinical patients in this research fully demonstrated that comprehensive treatment, including bronchial intervention and systemic anti‐infection, could greatly improve various indicators of TS patients.…”

Section: Discussionmentioning

confidence: 73%

Distribution and chemotactic mechanism of CD4⁺ T cells in traumatic tracheal stenosis

Feng

Chen

Wei

et al. 2023

Immunity Inflam & Disease

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A systemic and local inflammatory immune imbalance is thought to be the cause of traumatic tracheal stenosis (TS). However, with CD4+ T lymphocytes being the predominant immune cells in TS, the mechanism of action and recruitment has not been described. In our research, using flow cytometry, ELISA, immunofluorescence, and Transwell chamber assays, the expression, distribution, and potential chemotactic function of CD4+ T cells in TS patients were examined before and after treatment. The results showed that the untreated group had significantly more CD4+ T cells and their secreted TGF‐β1 than the treated group. Additionally, the untreated group's CD4+ T cells showed a significant rise in CCL22 and CCL1, as well as a larger proportion of CCR4 and CCR8. CD4+ T cells and CD68+ macrophages located in TS also expressed CCL1 and CCL22. In vitro, anti‐CCL1 and anti‐CCL22 can partially block the chemoattractant effect of TS bronchoalveolar lavage (BAL) on purified CD4+ T cells. The findings of this study indicated that TS contained unbalanced CD4 immune cells that were actively recruited locally by CCR4/CCL22 and CCR8/CCL1. As a result, it is anticipated that CD4 immune rebalancing can serve as a novel treatment for TS.

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“…HATs acetylate histones, which result in chromatin unwinding at specific sites, thereby increase the binding of transcription factors and RNA polymerase to DNA and promote inflammatory gene transcription, while HDACs remove the acetyl groups from the histone tails and inhibit the transcription of inflammatory genes ( 30 , 31 ). Endotracheal intubation or tracheotomy may cause an airway inflammatory response that is associated with changes in HDAC (mainly HDAC2) activity ( 19 , 32 ). Distinct subtypes of HDACs catalyze different patterns of deacetylation and regulate different genes, thereby generating different effects ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Expression of histone deacetylase 2 in tracheal stenosis models and its relationship with tracheal granulation tissue proliferation

et al. 2021

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The current treatments for benign tracheal stenosis are inefficient. The present study examined the expression of histone deacetylase 2 (HDAC2) in different tracheal stenosis models and explored its association with the proliferation of tracheal granulation tissue and its ability to constitute a potential therapy for tracheal stenosis. Animal tracheal stenosis models were established, as indicated by hematoxylin and eosin (H&E) staining. A total of 24 New Zealand White rabbits were randomly divided into control, erythromycin, budesonide and vorinostat groups. Stenotic tracheal tissues were collected on day 11 after drug administration for 10 days. The degree of tracheal stenosis in each group was calculated, and pathological alterations were observed using H&E staining. The mRNA expression of HDAC2, interleukin-8 (IL-8), transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) was examined via reverse transcription-quantitative PCR. The protein expression of HDAC2 was examined via immunofluorescence, while the expression of type I and type III collagen was assessed using immunohistochemistry. The results of the present study demonstrated that tracheal epithelial hyperplasia in the erythromycin group was improved, the degree of hyperplasia being the lowest among all groups, and tracheal stenosis was reduced compared with the control group. In the vorinostat group, tracheal epithelial tissue hyperplasia was aggravated and stenosis was increased. The HDAC2 mRNA and protein levels were increased and decreased in the erythromycin and vorinostat groups, respectively. In contrast, the IL-8 mRNA expression levels were decreased and increased in the erythromycin and vorinostat groups, respectively. TGF-β1, VEGF, type I and type III collagen expression was decreased in the erythromycin group, while TGF-β1, VEGF and type III collagen expression was increased in the vorinostat group. Compared with the control, the budesonide group did not exhibit any alterations in all of the indicators examined, including TGF-β1, VEGF, IL-8, HDAC2 and collagen. Erythromycin treatment upregulated the expression of HDAC2, inhibited the inflammatory responses and reduced the proliferation of tracheal granulation tissue. In contrast, vorinostat treatment downregulated HDAC2 expression, promoted the inflammatory responses and increased the proliferation of tracheal granulation tissue. These results suggest that regulating HDAC2 may be used as a potential treatment for benign tracheal stenosis.

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Role of Erythromycin-Regulated Histone Deacetylase-2 in Benign Tracheal Stenosis

Cited by 11 publications

References 36 publications

Antifibrotic Role of Nintedanib in Tracheal Stenosis After a Tracheal Wound

Antifibrotic Role of Nintedanib in Tracheal Stenosis After a Tracheal Wound

Distribution and chemotactic mechanism of CD4⁺ T cells in traumatic tracheal stenosis

Expression of histone deacetylase 2 in tracheal stenosis models and its relationship with tracheal granulation tissue proliferation

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Role of Erythromycin-Regulated Histone Deacetylase-2 in Benign Tracheal Stenosis

Cited by 11 publications

References 36 publications

Antifibrotic Role of Nintedanib in Tracheal Stenosis After a Tracheal Wound

Antifibrotic Role of Nintedanib in Tracheal Stenosis After a Tracheal Wound

Distribution and chemotactic mechanism of CD4+ T cells in traumatic tracheal stenosis

Expression of histone deacetylase 2 in tracheal stenosis models and its relationship with tracheal granulation tissue proliferation

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Distribution and chemotactic mechanism of CD4⁺ T cells in traumatic tracheal stenosis