title: Hydrogen Sulfide and Carbon Monoxide Protect Gastric Mucosa Compromised by Mild Stress Against Alendronate Injury.
abstract: Alendronate is an inhibitor of osteoclast-mediated bone resorption, but its clinical utility is limited due to gastrointestinal complications including bleeding erosions.
  
  
  
  We studied whether potent vasodilators hydrogen sulfide (H2S) and carbon monoxide (CO) can protect against alendronate-induced gastric lesions in rats exposed to mild stress.
  
  
  
  Three series (A, B, and C) of Wistar rats received alendronate (150-700 mg/kg i.g., series A) with or without NaHS (5 mg/kg), H2S donor or CORM-2 (5 mg/kg) releasing CO administered i.g. 30 min before alendronate administration (series B) in rats exposed for 3 days before alendronate administration to mild stress (series C). The area of gastric lesions was assessed by planimetry, the gastric blood flow (GBF) was determined by H2-gas clearance technique, and H2S production via CSE/CBS/3-MST activity and the gastric expression of HO-1, HO-2, HIF-1α, NF-κB, iNOS, COX-2, IL-1β, TNF-α, GPx-1 and SOD-2 were analyzed by qPCR or Western blot.
  
  
  
  Alendronate dose-dependently produced gastric mucosal lesions and significantly decreased GBF, and these effects were exacerbated by mild stress. NaHS and CORM-2 significantly reduced the alendronate-induced gastric lesions in non-stressed and stressed animals, but only NaHS but not CORM-2 raised H2S production. NaHS and CORM-2 inhibited gastric expression of HIF-1α protein and HO-1, HIF-1α, NF-κB, COX-2, iNOS, IL-1β, TNF-α mRNAs but failed to affect those of HO-2, GPx-1, and SOD-2.
  
  
  
  Both H2S and CO released from their donors, NaHS and CORM-2, protect gastric mucosa compromised by stress against alendronate-induced gastric damage via mechanism involving downregulation of HIF-1α, NF-κB and proinflammatory factors COX-2, iNOS, IL-1β, and TNF-α.
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Cracow, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Magierowski
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Cracow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Magierowska
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Cracow, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Szmyd
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Cracow, Poland.|Division of Molecular Biology and Clinical Genetics, Department of Medicine, Jagiellonian University Medical College, 8 Skawinska Street, 31-066, Cracow, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Surmiak
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Cracow, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Sliwowski
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Cracow, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Kwiecien
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Cracow, Poland. mpbrzozo@cyf-kr.edu.pl.
authors.forename: Tomasz
authors.identifier: 0000-0002-5805-0065
authors.initials: T
authors.lastname: Brzozowski
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics; D064426:Gasotransmitters / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000187:drug effects / Q000235:genetics; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000187:drug effects / Q000235:genetics; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000235:genetics; D009942:Organometallic Compounds / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D013315:Stress, Psychological; D013440:Sulfides / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000187:drug effects / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology*; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2
chemical_list: D019386:Alendronate; D050071:Bone Density Conservation Agents; D002248:Carbon Monoxide; D051546:Cyclooxygenase 2; D064426:Gasotransmitters; D005979:Glutathione Peroxidase; D006419:Heme Oxygenase (Decyclizing); D006862:Hydrogen Sulfide; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D009942:Organometallic Compounds; D020011:Protective Agents; D012333:RNA, Messenger; D013440:Sulfides; D013482:Superoxide Dismutase; D014665:Vasodilator Agents; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2; C497444:Hif1a protein, rat; C000594089:IL1B protein, rat; C447082:tricarbonyldichlororuthenium (II) dimer; C496318:Nos2 protein, rat; C491523:Hmox1 protein, rat; C105245:heme oxygenase-2; C489691:Ptgs2 protein, rat; C025451:sodium bisulfide; C000722069:Gpx1 protein, rat
keywords: Alendronate; Carbon monoxide; Gastric blood flow; Gastroprotection; Hydrogen sulfide; Hypoxia-inducible factor-1α