Temporal and spatial dependence of inflammatory biomarkers and suppression by fluvastatin in dextran sodium sulfate-induced rat colitis model.
BACKGROUND
Dextran sodium sulfate (DSS)-induced colitis in rats is widely used as an experimental model for elucidating the etiology of ulcerative colitis (UC) and developing its novel remedy. We investigated the temporal and spatial changes in inflammatory mediators such as tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) in the regions of rectum and distal colon and examined whether statins, which were designed to lower plasma cholesterol levels, influenced those mediators.


METHODS
Colitis was induced in rats by oral administration of 5 % DSS for 5 days, followed by 2 % DSS for 10 days. 5 % DSS rats were treated with fluvastatin (20 mg/kg) concomitantly for 5 days. The expression of inflammatory mediators of a sequence of four regions in rectum (R) and distal colon (D0, D1, and D2) was determined by quantitative RT-PCR.


RESULTS
The peak of colitic damage, which was confirmed clinically and histopathologically, was found on days 4-6. The expression of TNF-α, iNOS, cytokine-induced neutrophil chemoattractant-1, interleukin (IL)-1β, and IL-6 mRNA increased in R time dependently, showing the peak on days 4-6, and then decreased thereafter. The levels of mRNAs reduced from R to D0, D1, and D2 region dependently. Fluvastatin decreased the expression of these markers in addition to the prevention of DSS-induced damage.


CONCLUSIONS
Results demonstrated that the expression of inflammatory biomarkers had time and region specificity and was markedly inhibited by fluvastatin. To obtain a precise drug effect for UC, it is important to elucidate the temporal and spatial dependence of inflammatory biomarkers in DSS colitis model.
Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan, oishim@hirakata.kmu.ac.jp.
Masaharu
M
Oishi
Katsuji
K
Tokuhara
Hirokazu
H
Miki
Yoshito
Y
Tanaka
So
S
Yamaki
Masaki
M
Kaibori
Katsuhiko
K
Yoshizawa
Takashi
T
Yuri
Emi
E
Yoshigai
Mikio
M
Nishizawa
Tadayoshi
T
Okumura
A-Hon
AH
Kwon
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015415:Biomarkers; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D053583:Interleukin-1beta; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000077340:Fluvastatin; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II