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Oxidative gastric mucosal damage induced by ischemia/reperfusion and the mechanisms of its prevention by carbon monoxide-releasing tricarbonyldichlororuthenium (II) dimer.
Free Radic Biol Med. 2019 12; 145:198-208.FR

Abstract

Endogenous gaseous mediators, such as nitric oxide, hydrogen sulfide or carbon monoxide (CO) are known to exert anti-inflammatory and anti-oxidative activity due to modulation of various molecular pahtways. Therefore, we aimed to investigate if CO released from tricarbonyldichlororuthenium (II) dimer (CORM-2) prevents gastric mucosa against ischemia/reperfusion (I/R)-induced injury in male Wistar rats. Animals were pretreated i.g. With vehicle (DMSO and saline, 1:10), CORM-2 (1, 5 or 10 mg/kg) or zinc protoporphyrin IX (ZnPP, 10 mg/kg i.p.), the HMOXs inhibitor. In separate series, rats were pretreated with CORM-2 (5 mg/kg) applied in combination with glibenclamide (10 mg/kg i.g.), NG-nitro-l-arginine (L-NNA, 20 mg/kg i.p.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 mg/kg i.p.) or indomethacin (5 mg/kg i.p.). I/R-injuries were induced by clamping celiac artery for 30 min (I) followed by removal of the clamp to obtain R for 3 h. The macroscopic and microscopic area of gastric damage, mucus production and protein expression for HMOX-1/Nrf-2 was determined by planimetry, histology and immunohistochemistry, respectively. Gastric mucosal HMOX-1, HMOX-2, COX-1, COX-2, Kir6.1, Sur2, sGC-α1, sGC-α2, iNOS and eNOS mRNA expression was assessed by real-time PCR. COHb in blood and gastric mucosal CO concentration was analyzed by gas chromatography. Serum content of TGF-β1, TGF-β2, TGF-β3, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-α, IFN-γ, GM-CSF was evaluated using Luminex platform. PGE2 concentration and 8-hydroxyguanozine (8-OHG) concentration in gastric mucosa was determined by ELISA. Exposure to I/R induced extensive hemorrhagic erosions in gastric mucosa pretreated with vehicle as compared with intact rats and the area of this gastric damage was reduced by pretreatment with CORM-2 (5 mg/kg i.g.). This effect of CO donor was accompanied by the increased PGE2 content and a significant decrease in 8-OHG and expression of pro- and anti-inflammatory markers mRNA and proteins. Concurrent treatment of CORM-2 with glibenclamide, L-NNA, ODQ but not with indomethacin significantly increased the area of I/R-induced injury and significantly decreased GBF as compared with the group treated with CORM-2 alone. We conclude that CO releasing CORM-2 prevents gastric mucosal oxidative damage induced by I/R improving GBF, decreasing DNA oxidation and inflammatory response on systemic level. This CO-gastroprotection is mediated by the activity of sGC, NOS and K-ATP channels. CO delivered from its donor maintained physiological gastric mucosal PGE2 concentration but the involvement of endogenous COX in beneficial activity of this gaseous mediator at least in this model is questionable.

Authors+Show Affiliations

Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland; Department of Forensic Toxicology, Institute of Forensic Research, Cracow, Poland.Department of Forensic Medicine, Medical University of Lublin, Lublin, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Human Genome Variation Research Group & Genomics Centre, Malopolska Centre of Biotechnology, Jagiellonian University, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.Department of Physiology, Jagiellonian University Medical College, Cracow, Poland. Electronic address: m.magierowski@uj.edu.pl.

Pub Type(s)

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

Language

eng

PubMed ID

31568823

Citation

Magierowska, Katarzyna, et al. "Oxidative Gastric Mucosal Damage Induced By Ischemia/reperfusion and the Mechanisms of Its Prevention By Carbon Monoxide-releasing Tricarbonyldichlororuthenium (II) Dimer." Free Radical Biology & Medicine, vol. 145, 2019, pp. 198-208.
Magierowska K, Korbut E, Hubalewska-Mazgaj M, et al. Oxidative gastric mucosal damage induced by ischemia/reperfusion and the mechanisms of its prevention by carbon monoxide-releasing tricarbonyldichlororuthenium (II) dimer. Free Radic Biol Med. 2019;145:198-208.
Magierowska, K., Korbut, E., Hubalewska-Mazgaj, M., Surmiak, M., Chmura, A., Bakalarz, D., Buszewicz, G., Wójcik, D., Śliwowski, Z., Ginter, G., Gromowski, T., Kwiecień, S., Brzozowski, T., & Magierowski, M. (2019). Oxidative gastric mucosal damage induced by ischemia/reperfusion and the mechanisms of its prevention by carbon monoxide-releasing tricarbonyldichlororuthenium (II) dimer. Free Radical Biology & Medicine, 145, 198-208. https://doi.org/10.1016/j.freeradbiomed.2019.09.032
Magierowska K, et al. Oxidative Gastric Mucosal Damage Induced By Ischemia/reperfusion and the Mechanisms of Its Prevention By Carbon Monoxide-releasing Tricarbonyldichlororuthenium (II) Dimer. Free Radic Biol Med. 2019;145:198-208. PubMed PMID: 31568823.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxidative gastric mucosal damage induced by ischemia/reperfusion and the mechanisms of its prevention by carbon monoxide-releasing tricarbonyldichlororuthenium (II) dimer. AU - Magierowska,Katarzyna, AU - Korbut,Edyta, AU - Hubalewska-Mazgaj,Magdalena, AU - Surmiak,Marcin, AU - Chmura,Anna, AU - Bakalarz,Dominik, AU - Buszewicz,Grzegorz, AU - Wójcik,Dagmara, AU - Śliwowski,Zbigniew, AU - Ginter,Grzegorz, AU - Gromowski,Tomasz, AU - Kwiecień,Sławomir, AU - Brzozowski,Tomasz, AU - Magierowski,Marcin, Y1 - 2019/09/27/ PY - 2019/07/15/received PY - 2019/09/25/revised PY - 2019/09/26/accepted PY - 2019/10/1/pubmed PY - 2020/9/4/medline PY - 2019/10/1/entrez KW - Carbon monoxide KW - DNA oxidation KW - Gastric mucosa KW - Ischemia/reperfusion SP - 198 EP - 208 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 145 N2 - Endogenous gaseous mediators, such as nitric oxide, hydrogen sulfide or carbon monoxide (CO) are known to exert anti-inflammatory and anti-oxidative activity due to modulation of various molecular pahtways. Therefore, we aimed to investigate if CO released from tricarbonyldichlororuthenium (II) dimer (CORM-2) prevents gastric mucosa against ischemia/reperfusion (I/R)-induced injury in male Wistar rats. Animals were pretreated i.g. With vehicle (DMSO and saline, 1:10), CORM-2 (1, 5 or 10 mg/kg) or zinc protoporphyrin IX (ZnPP, 10 mg/kg i.p.), the HMOXs inhibitor. In separate series, rats were pretreated with CORM-2 (5 mg/kg) applied in combination with glibenclamide (10 mg/kg i.g.), NG-nitro-l-arginine (L-NNA, 20 mg/kg i.p.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 mg/kg i.p.) or indomethacin (5 mg/kg i.p.). I/R-injuries were induced by clamping celiac artery for 30 min (I) followed by removal of the clamp to obtain R for 3 h. The macroscopic and microscopic area of gastric damage, mucus production and protein expression for HMOX-1/Nrf-2 was determined by planimetry, histology and immunohistochemistry, respectively. Gastric mucosal HMOX-1, HMOX-2, COX-1, COX-2, Kir6.1, Sur2, sGC-α1, sGC-α2, iNOS and eNOS mRNA expression was assessed by real-time PCR. COHb in blood and gastric mucosal CO concentration was analyzed by gas chromatography. Serum content of TGF-β1, TGF-β2, TGF-β3, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-α, IFN-γ, GM-CSF was evaluated using Luminex platform. PGE2 concentration and 8-hydroxyguanozine (8-OHG) concentration in gastric mucosa was determined by ELISA. Exposure to I/R induced extensive hemorrhagic erosions in gastric mucosa pretreated with vehicle as compared with intact rats and the area of this gastric damage was reduced by pretreatment with CORM-2 (5 mg/kg i.g.). This effect of CO donor was accompanied by the increased PGE2 content and a significant decrease in 8-OHG and expression of pro- and anti-inflammatory markers mRNA and proteins. Concurrent treatment of CORM-2 with glibenclamide, L-NNA, ODQ but not with indomethacin significantly increased the area of I/R-induced injury and significantly decreased GBF as compared with the group treated with CORM-2 alone. We conclude that CO releasing CORM-2 prevents gastric mucosal oxidative damage induced by I/R improving GBF, decreasing DNA oxidation and inflammatory response on systemic level. This CO-gastroprotection is mediated by the activity of sGC, NOS and K-ATP channels. CO delivered from its donor maintained physiological gastric mucosal PGE2 concentration but the involvement of endogenous COX in beneficial activity of this gaseous mediator at least in this model is questionable. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/31568823/Oxidative_gastric_mucosal_damage_induced_by_ischemia/reperfusion_and_the_mechanisms_of_its_prevention_by_carbon_monoxide_releasing_tricarbonyldichlororuthenium__II__dimer_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(19)31177-3 DB - PRIME DP - Unbound Medicine ER -