Time-dependent course of gastric ulcer healing and molecular markers profile modulated by increased gastric mucosal content of carbon monoxide released from its pharmacological donor.

Abstract

BACKGROUND AND PURPOSE:

Besides hydrogen sulfide (H2S) and nitric oxide (NO), carbon monoxide (CO) contributes to the maintenance of gastric mucosal integrity. We investigated increased CO bioavailability effects on time-dependent dynamics of gastric ulcer healing mediated by particular growth factors, anti-inflammatory and molecular pathways.

EXPERIMENTAL APPROACH:

Wistar rats with gastric ulcers induced by serosal acetic acid application (day 0) were treated i.g. throughout 3, 6 or 14 days with vehicle or CO-releasing tricarbonyldichlororuthenium (II) dimer (CORM-2, 2.5 mg/kg). Gross and microscopic alterations in gastric ulcer size and gastric blood flow (GBF) at ulcer margin were determined by planimetry, histology and laser flowmetry, respectively. Gastric mRNA/protein expressions of platelet derived growth factors (PDGFA-D), insulin-like growth factor (IGF-1), epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGFA) and their receptors, heme oxygenases (HMOX), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX-2), hypoxia inducible factor (HIF)-1α, anti-inflammatory annexin-1 and transforming growth factor (TGF-β1) were assessed by real-time PCR or Western blot. TGF-β1-3 and IL-10 plasma concentration were measured using Luminex platform. Prostaglandin E2 content at ulcer margin was assessed by ELISA.

KEY RESULTS:

CORM-2 decreased ulcer area and increased GBF after 6 and 14 days of treatment comparing to vehicle. CO donor upregulated HGF, HGFr, VEGFR1, VEGFR2, TGF-β1, annexin-1 and maintained increased IGF-1, PDGFC and EGF expression at various time-intervals of ulcer healing. TGF-β3 and IL-10 plasma concentration were significantly increased after COMR-2 vs. vehicle.

CONCLUSIONS:

CO time-dependently accelerates gastric ulcer healing and raises GBF at ulcer margin by mechanism involving subsequent upregulation of anti-inflammatory, growth promoting and angiogenic factors response, not observed physiologically.

• Authors: Katarzyna Magierowska, Dominik Bakalarz, Dagmara Wójcik, Anna Chmura, Magdalena Hubalewska-Mazgaj, Sabina Licholai, Edyta Korbut, Slawomir Kwiecien, Zbigniew Sliwowski, Grzegorz Ginter, Tomasz Brzozowski, Marcin Magierowski
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 163 Pg. 71-83 (05 2019) ISSN: 1873-2968 [Electronic] England
• PMID: 30753813 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Intercellular Signaling Peptides and Proteins
• Organometallic Compounds
• tricarbonyldichlororuthenium (II) dimer
• Carbon Monoxide

Topics

• Animals
• Carbon Monoxide (metabolism)
• Dose-Response Relationship, Drug
• Drug Liberation (drug effects, physiology)
• Gastric Mucosa (drug effects, metabolism, pathology)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Male
• Organometallic Compounds (administration & dosage, metabolism)
• Rats
• Rats, Wistar
• Stomach Ulcer (drug therapy, metabolism, pathology)
• Time Factors