J. Luo1, R. Martins1, K. Poulikidis1, K. Patel1, R. Lebovics1, M. Latif1, F. Bhora1 1Hackensack Meridian Health, Surgery, Edison, NEW JERSEY, USA
Introduction:
Tracheal stenosis (TS) occurs most commonly due to iatrogenic causes, with mild-moderate stenosis occurring in 5-20% of patients with prolonged intubation. While the mainstay of treatment of tracheal stenosis is endoscopic ablation, most patients require repeated interventions to achieve and maintain airway patency. There is a need for a pharmacological adjunct to consolidate interventional management and decrease the need for repeated procedures.
Our team has recent uncovered molecular and genetic insights demonstrating that TS is driven by epithelial hyperkeratinization and hyperproliferation causing granulation tissue development. Biologically active retinoic acid (RA) is known to favorably affect these pathophysiological pathways.
Thus, we examined the transcriptomic profiles of TS granulation tissue with the aim of exploring the dysregulation of genes associated with key RA-related cellular pathways.
Methods:
Eleven samples from adult patients with severe, recalcitrant iatrogenic TS were included in this study after IRB approval. Biopsies of tracheal granulation tissue were collected at the time of endoscopic intervention.
Next-generation RNA sequencing was performed, and differential gene expression was determined between diseased tissue and normal control data from publicly accessible data repositories.
We identified dysregulated genes using the following criteria: fold change ≥ 1.5 and Bonferroni p-value < 0.05. For this study, we focused on genes specifically related to RA metabolism and cellular activity.
Results:
The tracheal granulation tissue biopsy samples revealed transcriptomic evidence of dysregulated RA metabolism (Figure), including decreased synthesis and increased degradation, resulting in an RA deficient state locally.
A RA responsive gene (RARRES1) was downregulated, and a RA receptor gene (RARG) was upregulated, indicating a deficiency of RA cellular activity within tracheal granulation tissue.
Genes that inhibit RA synthesis were upregulated (RDH12, AKR1B10, AKR1B15, and DHRS1), while a key gene responsible for activating stored RA was downregulated (LPL). Concurrently, genes responsible for RA degradation and inactivation were upregulated (CYP27C1, CYP2CP, and CYP2W1).
Conclusion:
The pathophysiology of iatrogenic TS involves dysregulations of RA metabolism, including decreased synthesis and increased degradation, resulting in an RA deficient state locally. Administration of RA may provide an adjunctive pharmacological option in the treatment of subglottic and tracheal stenosis, and may also be used prophylactically after airway procedures. Our future studies entail small animal tracheal stenosis models involving treatment with novel inhalational delivery methods for retinoic acid compounds.