Activation of nuclear factor-kappa B and effects of pyrrolidine dithiocarbamate on TNBS-induced rat colitis.

Abstract

AIM:

To explore the changes of nuclear factor-kappa B (NF-kappaB) DNA-binding activity, the expression of intercellular adhesion molecule-1 (ICAM-1) regulated by NF-kappaB at various times and to evaluate the effects of pyrrolidine dithiocarbamate (PDTC) on trinitrobenzene sulfonic acid (TNBS)-induced rat colitis.

METHODS:

TNBS of 0.6 mL was mixed with ethanol of 0.3 mL solution and instilled into the lumen of the rat colon. The rat models were divided into 6 groups, which were killed at 24 h, 3, 7, 14, and 21 d after enema. Colonic inflammation and damage were assessed by macroscopical and histological criteria. Activity of NF-kappaB DNA-binding was analyzed by electrophoresis mobility shift assays (EMSA). Expression of ICAM-1 was detected by in situ hybridization (ISH) and immunohistochemistry (IH). Then various doses of PDTC were injected into rat abdomen 30 min before enema with TNBS/ethanol as pretreatment. The rats were killed 4 h after enema and the colonic inflammation, myeloperoxidase (MPO) activity, malondialdehyde (MDA) level, and DNA-binding activity of NF-kappaB were assessed. Finally, PDTC was injected intraperitoneally after colitis was induced. Changes of morphology were assayed.

RESULTS:

During the first week, hyperemia, hemorrhage, edema and ulceration of the colonic mucosa appeared with predominant infiltration of leukocytes. Neutrophils, macrophages, lymphocytes infiltrated in mucosa and submucosa 14 d later. Fibroblasts and granuloma-like structures were also obviously seen. The binding activity of NF-kappaB began to increase at 24 h time point and reached a peak at 14 d, then decreased but still was higher than control group at 21 d (P<0.01). Levels of ICAM-1 mRNA and protein significantly elevated at 24 h and the peak was at 21 d. Pretreatment with PDTC could attenuate the development of inflammation but not by reducing NF-kappaB activity. This attenuation of inflammation had a positive relationship with the dose of PDTC. PDTC at the dose of 100 mg/kg had no therapeutic effect after colitis was induced.

CONCLUSION:

NF-kappaB activation is an important event that may be involved in acute and chronic inflammation development and may contribute to self-protection against early inflammation damage. NF-kappaB also regulates ICAM-1 expression during colonic inflammation. Pretreatment of PDTC may attenuate the inflammation development. But PDTC has no therapeutic effect after the colitis is induced.

• Authors: Ken Chen, You-Ming Long, Hui Wang, Lei Lan, Zhen-He Lin
• Journal: World journal of gastroenterology (World J Gastroenterol) Vol. 11 Issue 10 Pg. 1508-14 (Mar 14 2005) ISSN: 1007-9327 [Print] United States
• PMID: 15770728 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• NF-kappa B
• Pyrrolidines
• Thiocarbamates
• pyrrolidine dithiocarbamic acid
• Trinitrobenzenesulfonic Acid

Topics

• Animals
• Antioxidants (pharmacology)
• Colitis (chemically induced, metabolism, pathology, prevention & control)
• Male
• NF-kappa B (metabolism)
• Pyrrolidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Thiocarbamates (pharmacology)
• Trinitrobenzenesulfonic Acid