, Volume 17, Issue 6, pp 641–662 | Cite as

Mechanisms of acute and chronic intestinal inflammation induced by indomethacin

  • Tamaki Yamada
  • Edwin Deitch
  • Robert D. Specian
  • Michael A. Perry
  • R. Balfour Sartor
  • Matthew B. Grisham
Original Articles


The objective of this study was to characterize the mechanisms of acute and chronic intestinal mucosal injury and inflammation induced by subcutaneously injected indomethacin (Indo). One injection of Indo (7.5 mg/kg) produced acute injury and inflammation in the distal jejunum and proximal ileum that were maximal at three days and completely resolved within one week. Two daily subcutaneous injections of Indo produced a more extensive and chronic inflammation that lasted in an active form in more than 75% of the rats for at least two weeks. Epithelial injury, as measured by enhanced mucosal permeability, was significantly elevated only at one day in the acute model (one injection) but was persistently elevated in the chronic model (two injections). Bile duct ligation completely attenuated increased mucosal permeability in the acute model, however, depletion of circulating neutrophils had no effect. Neither Indo (0–0.1 mg/ml) nor normal bile was cytotoxic to cultured rat intestinal epithelial cells; however, they synergistically promoted significant cytotoxicity. Bile collected from rats treated with Indo was cytotoxic towards the epithelial cells in a dose-dependent manner. Sulfasalazine and metronidazole (100 mg/kg/day, both) attenuated enhanced mucosal permeability in the chronic model. Massive bacterial translocation into the mesenteric lymph nodes, liver, and spleen following two injections of Indo was significantly attenuated by metronidazole. We conclude that: (1) a single injection of Indo produces acute intestinal mucosal injury and inflammation that resolve completely within three to seven days, whereas two daily injections of Indo produce both acute and chronic injury and inflammation, (2) enterohepatic circulation of Indo is important in promoting the acute phases of injury and inflammation, (3) circulating neutrophils do not play a role in the pathogenesis of this model, and (4) endogenous bacteria play an important role in exacerbating and/or perpetuating the chronic phases of injury and inflammation.


Indomethacin Metronidazole Sulfasalazine Mesenteric Lymph Node Bacterial Translocation 
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Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Tamaki Yamada
    • 1
  • Edwin Deitch
    • 2
  • Robert D. Specian
    • 3
  • Michael A. Perry
    • 4
  • R. Balfour Sartor
    • 5
  • Matthew B. Grisham
    • 1
  1. 1.Departments of Physiology and BiophysicsLouisiana State University Medical Center ShreveportLouisiana
  2. 2.Department of SurgeryLouisiana State University Medical Center ShreveportLouisiana
  3. 3.Departments of Cellular Biology and AnatomyLouisiana State University Medical Center ShreveportLouisiana
  4. 4.School of Physiology and PharmacologyUniversity of New South WalesSydneyAustralia
  5. 5.Department of Medicine, Immunology and Microbiology Division of Digestive DiseaseUniversity of North CarolinaChapel Hill

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