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Retinoic Acid: A Silver Bullet In The Adjunctive Management Of Tracheal Stenosis
Faiz Y. Bhora, Russell S. Martins, Kostantinos Poulikidis, Syed S. Razi, M. Jawad Latif, Killol Patel, Robert S. Lebovics, Jeffrey Luo;
Hackensack Meridian Health, Edison, NJ, USA
BACKGROUNDWhile the mainstay of treatment of subglottic or tracheal stenosis (TS) 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.
Recent molecular and genetic insights have revealed 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.
METHODSEleven adult patients with severe, recalcitrant 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.
RESULTSThe 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).
CONCLUSIONSThe pathophysiology of 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.
LEGEND: Figure: Key dysregulated genes involved in RA metabolism.
RDH12: retinol dehydrogenase 12;
AKR1B10: Aldo-keto reductase family 1 member B10;
AKR1B15: Aldo-keto reductase family 1 member B15;
DHRS1: Dehydrogenase/Reductase 1;
CYP27C1: Cytochrome P450 family 27 subfamily C member 1;
CYP2C9: Cytochrome P450 Family 2 Subfamily C Member 9;
CYP2W1: Cytochrome P450 Family 2 Subfamily W Member 1;
LPL: Lipoprotein lipase
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