Carbon monoxide released from its pharmacological donor, tricarbonyldichlororuthenium (II) dimer, accelerates the healing of pre-existing gastric ulcers
Carbon monoxide released from its pharmacological donor, tricarbonyldichlororuthenium (II) dimer, accelerates the healing of pre-existing gastric ulcers
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DOI：
10.1111/bph.13968
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发表时间：
2017-10-01
影响因子：
7.3
通讯作者：
Brzozowski, Tomasz
中科院分区：
文献类型：
--
作者：
Magierowski, Marcin;Magierowska, Katarzyna;Brzozowski, Tomasz
背景和目的一氧化碳(CO)是一种由血红素加氧酶(HOS)产生的气体介质，已被证明可预防应激、乙醇、阿司匹林和阿伦磷酸钠诱导的胃损伤，但其在胃溃疡愈合中的作用尚未完全阐明。我们研究了三羰基二氯铀二聚体(CORM-2)释放的CO是否会影响胃溃疡的愈合，并确定了这种愈合作用的机制。动物用RuCl3[2.5mg.kg(-1)igg.(-1)]、海敏(5mg.kg(-1)ig.g.)、Corm-2(0.1-10mg.kg(-1)ig.g.)治疗9天。单独或与锌原卟啉IX(锌原卟啉IX，10 mg·kg(-1)i.g)、1H-[1，2，4]恶二唑并[4，3-a]喹恶啉-1-酮(ODQ，5 mg·kg(-1)ig.)、N-G-硝基-L精氨酸(L-NNA，15 mg·kg(-1)i.g.)、吲哚美辛(5 mg.kg(-1)i.g.)或格列本脲(10 mg·kg(-1)i.g)。胃溃疡面积和胃血流量(GBF)分别在平面测量法、显微镜下和激光血流仪上测量。用实时荧光定量聚合酶链式反应和免疫印迹法检测胃黏膜EGF、EGF受体、VEGFA、HOS、核因子(红系)样2(Nrf2)、COX-2、低氧诱导因子(HIF)-1和促炎性iNOS、IL-1β和TNF-α的表达。上述作用可被光量子、吲哚美辛、L-NNA和格列本脲所减弱。CORM-2显著降低促炎标志物Nrf2/HO1和HIF-1的表达，上调EGF的表达。结论CORM-2释放的CO或HO1/Nrf2途径内源性产生的CO可能通过增加GBF、上调EGF表达和下调炎症反应来促进胃溃疡愈合。
Background and PurposeCarbon monoxide (CO), a gaseous mediator produced by haem oxygenases (HOs), has been shown to prevent stress-, ethanol-, aspirin- and alendronate-induced gastric damage; however, its role in gastric ulcer healing has not been fully elucidated. We investigated whether CO released from tricarbonyldichlororuthenium (II) dimer (CORM-2) can affect gastric ulcer healing and determined the mechanisms involved in this healing action.Experimental ApproachGastric ulcers were induced in Wistar rats by serosal application of acetic acid. Animals received 9days of treatment with RuCl3 [2.5 mg.kg(-1) intragastrically (i.g.)], haemin (5 mg.kg(-1) i.g.), CORM-2 (0.1-10 mg.kg(-1) i.g.) administered alone or with zinc protoporphyrin IX (ZnPP, 10 mg.kg(-1) i.g.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 mg.kg(-1) i.g.), N-G-nitro-l-arginine (l-NNA, 15 mg.kg(-1) i.g.), indomethacin (5 mg.kg(-1) i.g.) or glibenclamide (10 mg.kg(-1) i.g.). Gastric ulcer area and gastric blood flow (GBF) were assessed planimetrically, microscopically and by laser flowmeter respectively. Gastric mRNA/protein expressions of EGF, EGF receptors, VEGFA, HOs, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), COX-2, hypoxia-inducible factor (HIF)-1 and pro-inflammatory iNOS, IL-1 beta and TNF-alpha were determined by real-time PCR or Western blots.Key ResultsCORM-2 and haemin but not RuCl3 or ZnPP decreased ulcer size while increasing GBF. These effects were reduced by ODQ, indomethacin, l-NNA and glibenclamide. CORM-2 significantly decreased the expression of pro-inflammatory markers, Nrf2/HO1 and HIF-1, and up-regulated EGF.Conclusions and ImplicationsCO released from CORM-2 or endogenously produced by the HO1/Nrf2 pathway accelerates gastric ulcer healing via an increase in GBF, an up-regulation in EGF expression and down-regulation of the inflammatory response.