title: Integrative roles of transforming growth factor-alpha in the cytoprotection mechanisms of gastric mucosal injury.
abstract: BACKGROUND
  Transforming growth factor alpha (TGFalpha) protects against gastric mucosal injury and facilitates wound healing. However, its overexpression is known to induce hypertrophic gastropathy resembling Menetrier's disease in transgenic (TG) mice on an FVB background, as one of the authors reported previously. We studied another TGFalpha-expressing mouse line on a CD1 background, whose gastric mucosa appears normal. Since this TG mouse had a strong resistance to ethanol-induced gastric injury, we considered the long-term effect of TGFalpha on several gastric protection mechanisms.
  
  
  METHODS
  TGFalpha-expressing transgenic (TG) mouse lines bearing human TGFalpha cDNA under the control of the mouse metallothionein gene I promoter were generated on a CD1 mouse background, and analyzed their ethanol injury-resistant phenotypes produced by TGFalpha.
  
  
  RESULTS
  In the TG mucosa, blood flow was well maintained after ethanol injury. Further, neural and inducible types of NO synthases were consistently and widely expressed in the TG mucosa, compared with the limited distribution of neural type NO synthase in the luminal pit region of the wild-type (WT) mucosa. COX-2 and its upstream transcription factor NfkB were constitutively elevated in the TG mucosa even before ethanol administration, whereas they were induced in the same region of the WT mucosa only after ethanol injury. Two anti-apoptotic proteins, HSP70 and Bcl-2, were upregulated in the TG mucosa even before ethanol administration, while they were not expressed in the WT mucosa before the injury. Furthermore, pro-caspase 3 activation was inhibited in the TG mucosa, while it was converted to the active form in the WT mucosa following ethanol administration.
  
  
  CONCLUSIONS
  We conclude that TGFalpha maintains the gastric mucosal defense against gastric injury by integrating other cytoprotective mechanisms.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan. tkosone@med.gunma-u.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kosone
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takagi
authors.forename: Satoru
authors.initials: S
authors.lastname: Kakizaki
authors.forename: Naondo
authors.initials: N
authors.lastname: Sohara
authors.forename: Norio
authors.initials: N
authors.lastname: Horiguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Sato
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoneda
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
mesh_terms: D000818:Animals; D017209:Apoptosis; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019610:Cytoprotection / Q000502:physiology*; D015232:Dinoprostone / Q000032:analysis; D000431:Ethanol; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000378:metabolism; D013272:Stomach Diseases / Q000139:chemically induced / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D000431:Ethanol; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D015232:Dinoprostone