Acute indomethacin-induced jejunal injury in the rat: early morphological and biochemical changes.
OBJECTIVE
Gastrointestinal injury induced by nonsteroidal anti-inflammatory drugs includes smooth muscle contraction, endothelial cell injury, and neutrophil infiltration. The aim of this study was to correlate early morphological changes with those in the metabolism of arachidonic acid.


METHODS
Rats administered a single oral dose of indomethacin (15 mg/kg) or vehicle were killed and their intestines perfusion-fixed at 1, 2, 3, 6, and 48 hours after dosage. Serial sections of affected small intestine were immunostained for neutrophils, macrophages, actin, and fibrinogen. In addition, rats receiving either indomethacin (15 mg/kg) or vehicle were killed at 1 and 6 hours after dosage; blood and small intestinal tissue were assayed for blood thromboxane B2, intestinal tissue prostaglandin E2, and the intestinal production of leukotriene B4.


RESULTS
At 2-6 hours, both intravascular and extravascular fibrin deposition were evident at the villus tip, and vertical alignment of villus smooth muscle cells was prominent. Significant neutrophil infiltration associated with a significant increase in leukotriene production was observed 6 hours after dosage. The extracted prostaglandin E2 content that was suppressed at 1 hour had recovered by 6 hours, whereas the blood thromboxane B2 levels were suppressed throughout the experiment.


CONCLUSIONS
This study identifies an early neutrophil-independent phase of indomethacin-induced enteropathy that involves rapid cyclooxygenase inhibition and both microvascular and smooth muscle changes.
Nygård
G
G
University Department of Medicine, Royal Free Hospital School of Medicine, London.
Anthony
A
A
Piasecki
C
C
Trevethick
M A
MA
Hudson
M
M
Dhillon
A P
AP
Pounder
R E
RE
Wakefield
A J
AJ
D000818:Animals; D002465:Cell Movement; D015232:Dinoprostone / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology*; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013931:Thromboxanes / Q000097:blood
D013931:Thromboxanes; D007975:Leukotriene B4; D015232:Dinoprostone; D007213:Indomethacin