Kosone Takashi, Takagi Hitoshi, Kakizaki Satoru, Sohara Naondo, Horiguchi Norio, Sato Ken, Yoneda Masashi, Takeuchi Toshiyuki, Mori Masatomo
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
BMC Gastroenterol. 2006 Aug 1;6:22. doi: 10.1186/1471-230X-6-22.
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.
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.
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.
We conclude that TGFalpha maintains the gastric mucosal defense against gastric injury by integrating other cytoprotective mechanisms.
转化生长因子α（TGFα）可保护胃黏膜免受损伤并促进伤口愈合。然而，正如本文作者之一先前报道的那样，已知其过度表达会在FVB背景的转基因（TG）小鼠中诱发类似梅内特里耶病的肥厚性胃病。我们研究了另一种CD1背景下表达TGFα的小鼠品系，其胃黏膜看起来正常。由于这种TG小鼠对乙醇诱导的胃损伤具有很强的抵抗力，我们考虑了TGFα对几种胃保护机制的长期影响。
在CD1小鼠背景上构建了在小鼠金属硫蛋白基因I启动子控制下携带人TGFα cDNA的表达TGFα的转基因（TG）小鼠品系，并分析了TGFα产生的乙醇损伤抗性表型。
在TG黏膜中，乙醇损伤后血流得到良好维持。此外，与野生型（WT）黏膜腔窝区域神经型一氧化氮合酶分布有限相比，神经型和诱导型一氧化氮合酶在TG黏膜中持续且广泛表达。COX-2及其上游转录因子NfkB在TG黏膜中即使在给予乙醇之前就持续升高，而在WT黏膜的相同区域仅在乙醇损伤后才被诱导。两种抗凋亡蛋白HSP70和Bcl-2在TG黏膜中即使在给予乙醇之前就上调，而在损伤前WT黏膜中未表达。此外，TG黏膜中前半胱天冬酶3的激活受到抑制，而在给予乙醇后WT黏膜中其转化为活性形式。
我们得出结论，TGFα通过整合其他细胞保护机制来维持胃黏膜对胃损伤的防御。
