Gene expression profiles in COVID-19-associated tracheal stenosis indicate persistent anti-viral response and dysregulated retinol metabolism

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Abstract

Introduction

Coronavirus disease 2019 (COVID-19)-associated tracheal stenosis (COATS) may occur as a result of prolonged intubation during COVID-19 infection. We aimed to investigate patterns of gene expression in the tracheal granulation tissue of patients with COATS, leverage gene expression data to identify dysregulated cellular pathways and processes, and discuss potential therapeutic options based on the identified gene expression profiles.

Methods

Adult patients (age ≥ 18 years) presenting to clinics for management of severe, recalcitrant COATS were included in this study. RNA sequencing and differential gene expression analysis was performed with transcriptomic data for normal tracheal tissue being used as a control. The top ten most highly upregulated and downregulated genes were identified. For each of these pathologically dysregulated genes, we identified key cellular pathways and processes they are involved in using Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) applied via Database for Annotation, Visualization, and Integrated Discovery (DAVID).

Results

Two women, aged 36 years and 37 years, were included. The profile of dysregulated genes indicated a cellular response consistent with viral infection (CXCL11, PI15, CCL8, DEFB103A, IFI6, ACOD1, and DEFB4A) and hyperproliferation/hypergranulation (MMP3, CASP14 and HAS1), while downregulated pathways included retinol metabolism (ALDH1A2, RBP1, RBP4, CRABP1 and CRABP2).

Conclusion

Gene expression changes consistent with persistent viral infection and dysregulated retinol metabolism may promote tracheal hypergranulation and hyperproliferation leading to COATS. Given the presence of existing literature highlighting retinoic acid’s ability to favorably regulate these genes, improve cell-cell adhesion, and decrease overall disease severity in COVID-19, future studies must evaluate its utility for adjunctive management of COATS in animal models and clinical settings.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13104-024-06775-y.

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Most cited references 43

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Complications and consequences of endotracheal intubation and tracheotomy. A prospective study of 150 critically ill adult patients.

J Stauffer, Eric Olson, Rafe Petty (1980)

A prospective study of the complications and consequences of translaryngeal endotracheal intubation and tracheotomy was conducted on 150 critically ill adult patients. Adverse consequences occurred in 62 percent of all endotracheal intubations and in 66 percent of all tracheotomies during placement and use of the artificial airways. The most frequent problems during endotracheal intubation were excessive cuff pressure requirements (19 percent), self-extubation (13 percent) and inability to seal the airway (11 percent). Patient discomfort and difficulty in suctioning tracheobronchial secretions were very uncommon. Problems with tracheotomy included stomal infection (36 percent), stomal hemorrhage (36 percent), excessive cuff pressure requirements (23 percent) and subcutaneous emphysema or pneumomediastinum (13 percent). Complications of tracheotomy were judged to be more severe than those of endotracheal intubation. Follow-up studies of survivors revealed a high prevalence of tracheal stenosis after tracheotomy (65 percent) and significantly less after endotracheal intubation (19 percent)(p < 0.01). Thirty-nine of 41 (95 percent) patients with endotracheal intubation and 20 of 22 (91 percent) patients with tracheotomy had laryngotracheal injury at autopsy. Ulcers on the posterior aspect of the true vocal cords were found at autopsy in 51 percent of the patients who died after endotracheal intubation. There was no significant relationship between the duration of endotracheal intubation or tracheotomy and the over-all amount of laryngotracheal injury at autopsy, although patients with prolonged endotracheal intubation followed by tracheotomy had more laryngeal injury at autopsy (P = 0.06) and more frequent tracheal stenosis (P = 0.05) than patients with short-term endotracheal intubation followed by tracheotomy. Adverse effects of both endotracheal intubation and tracheotomy are common. The value of tracheotomy when an artificial airway is required for periods as long as three weeks is not supported by data obtained in this study.

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Postintubation tracheal stenosis. Treatment and results.

D. Wright, H Grillo, J C Wain … (1995)

A total of 503 patients underwent 521 tracheal resections and reconstructions for postintubation stenosis from 1965 through 1992. Fifty-three had had prior attempts at surgical resection, 51 others had undergone various forms of tracheal or laryngeal repair, and 45 had had laser treatment. There were 251 cuff lesions, 178 stomal lesions, 38 at both levels, and 36 of indeterminate origin. Sixty-two patients with major laryngeal injuries required complete resection of anterior cricoid cartilage and anastomosis of trachea to thyroid cartilage, and 117 had tracheal anastomosis to the cricoid. A cervical approach was used in 350, cervicomediastinal in 145, and transthoracic in 8. Length of resection was 1.0 to 7.5 cm. Forty-nine had laryngeal release to reduce anastomotic tension. A total of 471 patients (93.7%) had good (87.5%) or satisfactory (6.2%) results. Eighteen of 37 whose operation failed underwent a second reconstruction. Eighteen required postoperative tracheostomy or T-tube insertion for extensive or multilevel disease. Twelve died (2.4%). The most common complication, suture line granulations (9.7%), has almost vanished with the use of absorbable sutures. Wound infection occurred in 15 (3%) and glottic dysfunction in 11 (2.2%). Five had postoperative innominate artery hemorrhage. Resection and reconstruction offer optimal treatment for postintubation tracheal stenosis.

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Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment.

Benjamin Davis, Emily M. Stucke, M Khorki … (2016)

We recently identified a genome-wide genetic association of eosinophilic esophagitis (EoE) at 2p23 spanning the calpain 14 (CAPN14) gene, yet the causal mechanism has not been elucidated. We now show that recombinant CAPN14 cleaves a calpain-specific substrate and is inhibited by 4 classical calpain inhibitors: MDL-28170, acetyl-calpastatin, E-64, and PD151746. CAPN14 is specifically induced (>100-fold) in esophageal epithelium after IL-13 treatment. Epithelial cells overexpressing CAPN14 display impaired epithelial architecture, characterized by acantholysis, epidermal clefting, and epidermolysis. CAPN14 overexpression impairs epithelial barrier function, as demonstrated by decreased transepithelial resistance (2.1-fold) and increased FITC-dextran flux (2.6-fold). Epithelium with gene-silenced CAPN14 demonstrates increased dilated intercellular spaces (5.5-fold) and less organized basal cell layering (1.5-fold) following IL-13 treatment. Finally, CAPN14 overexpression results in loss of desmoglein 1 (DSG1) expression, whereas the IL-13-induced loss of DSG1 is normalized by CAPN14 gene silencing. Importantly, these findings were specific to CAPN14, as they were not observed with modulation of CAPN1 expression. These results, along with the potent induction of CAPN14 by IL-13 and genetic linkage of EoE to the CAPN14 gene locus, demonstrate a molecular and cellular pathway that contributes to T helper type 2 responses in mucosal epithelium.

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Author and article information

Contributors

Russell Seth Martins: russellseth.martins@hmhn.org

Faiz Y. Bhora: faiz.bhora@hmhn.org

Journal

Journal ID (nlm-ta): BMC Res Notes

Journal ID (iso-abbrev): BMC Res Notes

Title: BMC Research Notes

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-0500

Publication date (Electronic): 16 May 2024

Publication date PMC-release: 16 May 2024

Publication date Collection: 2024

Volume: 17

Electronic Location Identifier: 140

Affiliations

[1 ]Department of Surgery, Hackensack Meridian School of Medicine, Hackensack Meridian Health (HMH) Network, ( https://ror.org/04p5zd128) 08820 Edison, NJ USA

[2 ]Division of Surgical Oncology, Department of Surgery, Dyson Center for Cancer Care, Vassar Brothers Medical Center, Nuvance Health, ( https://ror.org/05g023586) 12601 Poughkeepsie, NY USA

[3 ]Division of Oral and Maxillofacial Surgery, Department of Surgery, Vassar Brothers Medical Center, Nuvance Health, ( https://ror.org/05g023586) 12601 Poughkeepsie, NY USA

[4 ]Division of Thoracic Surgery, Department of Surgery, Hackensack Meridian School of Medicine, Hackensack Meridian Health (HMH) Network– Central Region, ( https://ror.org/04p5zd128) 65 James Street, 08820 Edison, NJ USA

[5 ]Chief of Thoracic Surgery, Hackensack Meridian Health (HMH) Network– Central Region, Hackensack Meridian School of Medicine, ( https://ror.org/04p5zd128) 65 James Street, 08820 Edison, NJ USA

Article

Publisher ID: 6775

DOI: 10.1186/s13104-024-06775-y

PMC ID: 11100031

PubMed ID: 38755665

SO-VID: 1e0b60d7-8c85-4e77-8e45-b10f163cdc78

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 10 May 2023

Date accepted : 15 April 2024

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: coronavirus disease 2019,subglottic stenosis,molecular medicine,rna,endotracheal intubation,granulation tissue

Data availability:

ScienceOpen disciplines: Medicine

Keywords: coronavirus disease 2019, subglottic stenosis, molecular medicine, rna, endotracheal intubation, granulation tissue

Gene expression profiles in COVID-19-associated tracheal stenosis indicate persistent anti-viral response and dysregulated retinol metabolism

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Abstract

Introduction

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Results

Conclusion

Supplementary Information

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Novel Coronavirus Disease COVID-19

Most cited references 43

Complications and consequences of endotracheal intubation and tracheotomy. A prospective study of 150 critically ill adult patients.

Postintubation tracheal stenosis. Treatment and results.

Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment.

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