Introduction
Barrett’s esophagus (BE), the precursor of esophageal adenocarcinoma (EAC) develops due to gastroesophageal reflux disease (GERD). The prolonged exposure of esophagus to acidified gastroduodenal content (bile mixture, BM) predisposes physiological squamous epithelium to the transformation towards specialized intestinal metaplasia (SIM). We observed that in GERD-exposed squamous or metaplastic esophageal mucosa expression of heme oxygenase (HMOX1) is altered, based on clinical datasets analyses and rats-based experimental models. Enzymatic activity of HMOX1 generates endogenous carbon monoxide (CO) that contributes to the maintenance of gastrointestinal (GI) integrity. Interestingly, CO-prodrugs applied i.g. were shown to enhance gastric mucosal integrity. Most recently, we have been working on developing metal-free organic CO prodrugs belonging to different structural classes with tunable CO release rates. Some of these prodrugs are capable of triggered release (e.g. pH- or ROS-sensitive), mitochondrion-targeting, employing dual-triggers, and delivering more than one payload using a single prodrug. However, controlled release of CO, delivered by new class of organic CO prodrugs in the treatment or prevention of GERD-induced Barrett’s metaplasia development remains overlooked.
Aims & Methods
Thus, we aimed to evaluate if long-term i.g. treatment with tin protoporphyrin IX (SnPP) (HMOX-1 inhibitor) and novel CO prodrug, BW-CO-111, affects the development of GERD-induced BE, based on translational animal model. Wistar rats with esophagogastroduodenal anastomosis (EGDA) were treated for approx. 10 weeks with vehicle or BW-CO-111 (0.1-2 mg/kg i.g.), BW-CP-111 (0.5 mg/kg i.g.) as structural control without ability to release CO, or SnPP (5 mg/kg i.g.). Esophageal lesions index (ELI) was assessed macroscopically and microscopically. Molecular pattern of selected state-of-the-art BE-sensitive markers (such as e.g. KRT4, KRT8, KRT15) was determined by real-time PCR. Gastric secretion as a target for current proton pump inhibitors (PPIs)-based pharmacology of GERD was evaluated in rats equipped microsurgically with gastric fistulas.
Results
ELI score (chronic GERD-induced lesions) was decreased in groups treated i.g. with BW-CO-111 (0.5 mg/kg) but not with BW-CP-111 (0.5 mg/kg) or SnPP (5 mg/kg). BW-CO-111 maintained squamous epithelium-specific molecular pattern counteracting GERD-induced columnar epithelium specific alterations. Inhibition of HMOX1 by SnPP elevated while BW-CO-111 decreased gastric acid output.
Conclusion
We propose the new fundamental approach that HMOX-1/CO pathway activity is affected in esophageal mucosa exposed to GERD, predisposing to Barrett’s metaplasia development. Controlled i.g. delivery of CO, released from the new platform of organic CO prodrugs, counteracts this pathological phenomenon on molecular and macroscopic level. Additionally, CO released from BW-CO-111 is capable of decreasing gastric secretion mimicking PPIs effects. We also conclude that CO-based therapeutics could be considered as an alternative or additional treatment methods of GERD.
[Funding: National Science Centre, Poland (UMO-2019/33/B/NZ4/00616)]
References
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Disclosure
No conflict of interest