| セッション情報 |
The 4th International Forum
I Drug-associated GI Injury：Advances of the pathogenesis and recent clinical topics 1. Advances of the pathogenesis（b）Bacterial involvement
|
| タイトル |
IFI-1b-3：Importance of TLR4-dependent pathways for the pathogenesis and treatment of NSAID-induced enteropathy
|
| 演者 |
Watanabe Toshio（Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan） |
| 共同演者 |
Arakawa Tetsuo（Department of Gastroenterology, Osaka City University Graduate School of Medicine, Japan） |
| 抄録 |
NSAIDs cause small bowel damage with high frequency. Our study using capsule endoscopy has showed that more than half of chronic NSAID users had mucosal breaks in the small intestine. NSAIDs do not induce damage in the small intestine in germ-free animals, suggesting that enterobacteria is essential for the development of NSAID-induced enteropathy. We found that antibiotics such as ampicillin and aztreonam inhibited the damage, and decreased the number of Gram-negative bacteria in the rat small intestinal content, but vancomycin, which exhibited no activity against Gram-negative bacteria, had no preventive effect against damage. Interestingly, in mice with mutation of Toll-like receptor 4（TLR4）, a receptor of LPS, the damage and inflammatory responses such as overexpression of cytokines and neutrophil infiltration was markedly inhibited. TLR4-/- and MyD88-/- mice were also resistant to the damage. These results suggest that Gram-negative bacteria having invaded the small bowel mucosa activate TLR4 and induce excessive expression of cytokines such as tumor necrosis factor-alpha, leading to neutrophil infiltration and intestinal ulceration. Several experimental and clinical results support our hypothesis：probiotics such as Lactobacillus casei strain Shirota was effective for treatment of NSAID-induced small intestinal damage. Furthermore our data obtained from capsule endoscopic study demonstrated that rheumatoid arthritis patients who received anti-TNF therapy had less severe NSAID-induced enteropathy than those who did not receive such therapy. Our data thus suggest that the development of agents that modulate the TLR4/MyD88-dependent pathway could lead to new therapies for the prevention and treatment of NSAID-induced enteropathy. |
| 索引用語 |
|
