title: Increased gap density predicts weakness of the epithelial barrier in vivo by confocal laser endomicroscopy in indomethacin-induced enteropathy.
abstract: OBJECTIVE
  The intestinal epithelial barrier plays an important role in the pathogenesis of non-steroidal anti-inflammatory drug-induced enteropathy, and its disruption is often associated with increased cell shedding. The purpose of this report is to observe the gap density in indomethacin-induced small intestinal damage by confocal laser endomicroscopy (CLE) and to investigate the mechanisms involved in this process and how mucosal protectants improve intestinal epithelial barrier dysfunction. CLE is expected to provide a new way for evaluating non-steroidal anti-inflammatory drugs-induced enteropathy in humans and assessing drug efficacy.
  
  
  METHODS
  Using the new technique of CLE, we established a method to evaluate, in real time, intestinal damage after the administration of indomethacin in Wistar rats by investigating the gap density in the small intestine. The mucosal protectant teprenone and acid-suppressant rabeprazole were then given by gavage before and after the administration of indomethacin, and the mechanisms affecting the intestinal epithelial barrier were investigated.
  
  
  RESULTS
  Using CLE, gaps could be clearly observed and easily distinguished from goblet cells. Gap density was increased after the administration of indomethacin. During this process, the expression of tumor necrosis factor-α, nuclear factor-κB, and caspase-3 was up-regulated and the expression of tight junctions was down-regulated, which led to the damage of the epithelial barrier. Teprenone and rabeprazole could intervene in this pathway and protect the integrity of the epithelial barrier.
  
  
  CONCLUSIONS
  CLE can be objective, accurate, and real time in investigating gap density. Teprenone and rabeprazole can prevent indomethacin-induced intestinal lesions and protect the epithelial barrier by intervening in the tumor necrosis factor-α pathway. Gap density was expected to be an indicator of evaluating intestinal inflammation and drug efficacy.
authors.affiliation: Department of Gastroenterology, Qilu Hospital, Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, People's Republic of China, shisha81@126.com.
authors.forename: Sha
authors.initials: S
authors.lastname: Shi
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Fei-Xue
authors.initials: FX
authors.lastname: Chen
authors.forename: Xiu-li
authors.initials: XL
authors.lastname: Zuo
authors.forename: Yan-qing
authors.initials: YQ
authors.lastname: Li
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D000897:Anti-Ulcer Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D004224:Diterpenes / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology*; D007213:Indomethacin / Q000009:adverse effects*; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018613:Microscopy, Confocal; D064750:Rabeprazole / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D015415:Biomarkers; D004224:Diterpenes; D064750:Rabeprazole; C031049:geranylgeranylacetone; D007213:Indomethacin