Pathophysiological characteristics of dimethylnitrosamine-induced liver fibrosis in acute and chronic injury models: a possible contribution of KLF5 to fibrogenic responses.
Dimethylnitrosamine administration induces a rapid increase in collagen deposition with concomitant proliferation of hepatic stellate cells in rats. Here, we investigated the pathophysiological profiles of acute and chronic hepatic fibrosis states and attempted to determine the possible role of Kruppel-like factor-5 (KLF5) in this model. In acute study using a single drug injection, we observed a rapid transient increase of ALT and mRNA levels of KLF5 followed by increases in fibrosis-related genes. Repeated administration of dimethylnitrosamine once a week caused early damage with severe fibrosis and sustained hepatocyte injury, while intermittent injections at 2-week intervals induced only modest fibrosis from 3 weeks. Weekly administration also induced profound upregulation of collagen I, alpha-smooth muscle actin, and KLF5 mRNA. In contrast, such continued augmentation was not observed after intermittent injections; KLF5 increased only after 3 weeks. These results suggested that dimethylnitrosamine induced a rapid hepatic fibrogenic response with a possible participation of KLF5.
Ohara
Fumihiro
F
St Louis Laboratories, Pfizer Global Research and Development, Chesterfield, MO 63017, USA. fohara@asahi.email.ne.jp
Nii
Aisuke
A
Sakiyama
Yojiro
Y
Tsuchiya
Megumi
M
Ogawa
Shinji
S
D000199:Actins / Q000378:metabolism; D000208:Acute Disease; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002908:Chronic Disease; D024042:Collagen Type I / Q000378:metabolism; D004128:Dimethylnitrosamine; D004195:Disease Models, Animal; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation
D000199:Actins; D000410:Alanine Transaminase; D024042:Collagen Type I; D004128:Dimethylnitrosamine; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; C492215:Klf5 protein, rat; C498862:Acta2 protein, rat