Altered Prostasin (CAP1/Prss8) Expression Favors Inflammation and Tissue Remodeling in DSS-induced Colitis
Altered Prostasin (CAP1/Prss8) Expression Favors Inflammation and Tissue Remodeling in DSS-induced Colitis
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DOI：
10.1097/mib.0000000000000940
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发表时间：
2016-12-01
影响因子：
4.9
通讯作者：
Hummler, Edith
中科院分区：
文献类型：
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作者：
Keppner, Anna;Malsure, Sumedha;Hummler, Edith
背景：炎症性肠病(IBD)包括溃疡性结肠炎和克罗恩病，是上皮屏障功能受损的疾病。本研究旨在探讨前列腺素突变及结肠上皮钠通道活性降低是否易导致葡聚糖硫酸钠(DSS)诱导的实验性结肠炎。方法：对野生型、杂合型(fr(CR)/+)和纯合子(fr(CR)/fr(CR))前列腺素突变大鼠进行治疗7d后再治疗7d，并对其组织学、临床病理参数、炎症标志物mRNA转录本表达和钠转运体蛋白表达进行分析。结果：在本研究中，对大鼠fr(CR)/fr(CR)结肠进行了更详细的分析，发现隐窝和杯状细胞数量减少，局部血管发育不良，局部血管发育不良与杂合子(fr(CR)/+)和野生型窝产仔比较。2%DSS治疗7d后，fr(CR)/fr(CR)动物体重减轻，仅3d便达到最大腹泻评分和最高疾病活动度，细胞因子水平显著升高。组织学评分在所有组均显著增加，但fr(CR)/fr(CR)结肠进一步显示明显的组织学改变，几乎没有杯状细胞，固有层重排，并存在中性粒细胞、嗜酸性粒细胞和巨噬细胞。此外，fr(CR)/fr(CR)结肠显示出fr(CR)/+和野生型乳鼠所没有的溃疡和水肿症。恢复后，fr(CR)/fr(CR)大鼠的腹泻评分和疾病活动明显延迟，接近正常，但表现出严重的结构重构，尽管钠转运蛋白的表达没有变化。结论：总之，我们的结果表明，结肠前列腺素的表达对实验性结肠炎具有保护作用，因此可能是炎症性肠病发生发展的易感基因。
Background: Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease are diseases with impaired epithelial barrier function. We aimed to investigate whether mutated prostasin and thus, reduced colonic epithelial sodium channel activity predisposes to develop an experimentally dextran sodium sulfate (DSS)-induced colitis.Methods: Wildtype, heterozygous (fr(CR)/+), and homozygous (fr(CR)/fr(CR)) prostasin-mutant rats were treated 7 days with DSS followed by 7 days of recovery and analyzed with respect to histology, clinicopathological parameters, inflammatory marker mRNA transcript expression, and sodium transporter protein expression.Results: In this study, a more detailed analysis on rat fr(CR)/fr(CR) colons revealed reduced numbers of crypt and goblet cells, and local angiodysplasia, as compared with heterozygous (fr(CR)/+) and wildtype littermates. Following 2% DSS treatment for 7 days followed by 7 days recovery, fr(CR)/fr(CR) animals lost body weight, and reached maximal diarrhea score and highest disease activity after only 3 days, and strongly increased cytokine levels. The histology score significantly increased in all groups, but fr(CR)/fr(CR) colons further displayed pronounced histological alterations with near absence of goblet cells, rearrangement of the lamina propria, and presence of neutrophils, eosinophils, and macrophages. Additionally, fr(CR)/fr(CR) colons showed ulcerations and edemas that were absent in fr(CR)/+ and wildtype littermates. Following recovery, fr(CR)/fr(CR) rats reached, although significantly delayed, near-normal diarrhea score and disease activity, but exhibited severe architectural remodeling, despite unchanged sodium transporter protein expression.Conclusions: In summary, our results demonstrate a protective role of colonic prostasin expression against experimental colitis, and thus represent a susceptibility gene in the development of inflammatory bowel disease.