Influence of bacterial lipopolysaccharide on healing of chronic experimental ulcer in rat.
BACKGROUND
Lipopolysaccharides (LPS) are major components of the outer membrane of Gram-negative bacteria, which play a central role as potent endotoxins in the pathogenesis of the Gram-negative septicaemia. Although it is well known that large amounts of endotoxin may produce haemorrhagic lesions in the stomach, the effect of LPS on ulcer healing has not been fully clarified. The aim of the present study was to examine the effect of parenteral injection of LPS at different doses on the course of ulcer healing in rats.


METHODS
Gastric ulcers were induced in Wistar rats by serosal application of an acetic acid area. After ulcer induction, vehicle (saline) or E. coli-LPS was injected at various doses (0.1, 1 and 5 mg/kg i.p.) for 7 days. The animals were sacrificed on day 8 after ulcer induction and the following parameters were analysed; ulcer area (planimetry), gastric blood flow (GBF) (H2 gas clearance method), gastric secretion, plasma levels of proinflammatory cytokines such as IL-1beta and TNFalpha, mucosal gene expression for cyclooxygenases (COX-1/-2), apoptosis-related proteins (Bax, Bcl-2), TNFalpha, IL-1beta and vascular endothelial growth factor (VEGF).


RESULTS
Daily parenteral challenge with LPS resulted in a dose-dependent delay in ulcer healing with maximum observed at a dose of 5 mg/kg (12.14 +/- 1.2 mm2 versus 5.18 +/- 0.8 mm2 in the control group). The impairment of ulcer healing in LPS-treated rats was associated with a significant decrease in GBF, increased mRNA expression for IL-1beta, TNFalpha, the rise in plasma IL-1beta and TNFalpha levels, an overexpression of COX-2 and VEGF and imbalance in the ratio between pro-apoptotic Bax and antiapoptotic Bcl-2. The daily administration of 50 mg/kg pentoxifylline by itself failed to accelerate the ulcer healing but attenuated the deleterious effects of LPS on this healing.


CONCLUSIONS
1) Bacterial endotoxin impairs ulcer healing through the decrease in gastric mucosal blood flow, increased expression and release of proinflammatory cytokines IL-1beta and TNFalpha, the imbalance between pro- and anti-apoptotic members of Bcl-2 family via downregulation of antiapoptotic bcl-2, and 2) endotoxin leads to upregulation of genes for VEGF and COX-2, which fail to accelerate the ulcer healing.
Konturek
P C
PC
First Dept. of Medicine, University Erlangen-Nuremberg, Germany. peter.konturek@med1.imed.uni-erlangen.de
Brzozowski
T
T
Konturek
S J
SJ
Kwiecien
S
S
Dembinski
A
A
Hahn
E G
EG
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli; D005753:Gastric Mucosa / Q000098:blood supply; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D010431:Pentoxifylline / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects*
D016207:Cytokines; D008070:Lipopolysaccharides; D010431:Pentoxifylline