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

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

doi:10.1016/j.bcp.2019.02.011

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

Biochem Pharmacol. 2019 May:163:71-83. doi: 10.1016/j.bcp.2019.02.011. Epub 2019 Feb 10.

Affiliations

¹ Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
² Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland; Department of Forensic Toxicology, Institute of Forensic Research, 9 Westerplatte Street, 31-033 Cracow, Poland.
³ Department of Molecular Biology and Clinical Genetics, Jagiellonian University Medical College, 8 Skawinska Street, 31-066 Cracow, Poland.
⁴ Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland. Electronic address: m.magierowski@uj.edu.pl.

PMID: 30753813
DOI: 10.1016/j.bcp.2019.02.011

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.

Keywords: Angiogenesis; Carbon monoxide pharmacology; Gastric ulcer healing; Growth factors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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