Abstract
BackgroundTransforming growth factor α (TGFα) 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 TGFα-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 TGFα on several gastric protection mechanisms.MethodsTGFα-expressing transgenic (TG) mouse lines bearing human TGFα 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 TGFα.ResultsIn 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.ConclusionWe conclude that TGFα maintains the gastric mucosal defense against gastric injury by integrating other cytoprotective mechanisms.
Highlights
Transforming growth factor α (TGFα) protects against gastric mucosal injury and facilitates wound healing
Since the MT42 line displayed a surprising level of resistance to ethanol-induced injury to the gastric mucosa, we considered that it could be useful for exploring the non-proliferative effects of TGFα such as mucosal resistance to ethanol injury
The greatest thickness observed for the gastric wall and fundic glands were 3.50 ± 0.18 mm and 2.33 ± 0.20 mm, respectively, in the WT mice, and 3.85 ± 0.24 mm and 2.63 ± 0.16 mm, respectively, in the TG mice; there were no significant differences in the shape of the gastric mucosae and glands between the WT and TG mice
Summary
Transforming growth factor α (TGFα) protects against gastric mucosal injury and facilitates wound healing. 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 TGFα-expressing mouse line on a CD1 background, whose gastric mucosa appears normal. A number of cytoprotective compounds have been tested to evaluate their potency in resisting gastric injury, including gastrointestinal hormones, growth factors, prostaglandins, bioactive amines, and mild irritants such as capsaicin [2,3,4,5] Among these compounds, epidermal growth factor (EGF) family growth factors, notably transforming growth factor α (TGFα), have been reported as potent cytoprotective compounds against ethanol-, acetic acid-, or aspirin-induced gastric injury [2,4]. The EGF-R signal appears to mediate COX-2 induction in the gastric mucosa
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