Cholestasis with altered structure and function of hepatocyte tight junction and decreased expression of canalicular multispecific organic anion transporter in a rat model of colitis.
Cholestasis is frequently associated with inflammatory bowel disease. Because some cholestasis is resulted from altered hepatocyte tight junctions (TJs) or the canalicular multispecific organic anion transporter, we have investigated the following topics in a rat model of inflammatory bowel disease: (1) alterations in hepatocyte TJs and in the canalicular multispecific organic anion transporter, (2) etiologic factors for cholestasis, and (3) effects of antibiotics on cholestasis. Rats with trinitrobenzene sulfonic acid-induced colitis were studied 24 hours after treatment. Hepatocyte TJs and the canalicular multispecific organic anion transporter were evaluated by immunostaining for TJ-associated proteins, 7H6 and ZO-1, and multidrug resistance protein 2 (mrp2). To investigate etiologic factors causing cholestasis, portal endotoxin and proinflammatory cytokines were examined. The effects of polymyxin B, penicillin G, or metronidazole on immunostaining for 7H6, ZO-1, mrp2, and cholestasis were investigated. (1) Immunostaining for 7H6 and ZO-1 colocalized outlining the bile canaliculi and immunostaining for mrp2 localized on the canalicular membrane in controls. Treatment with trinitrobenzene sulfonic acid induced significant cholestasis and caused translocation of immunostaining for 7H6, but not that for ZO-1, to the cytoplasm and diminished immunostaining for mrp2 on the canaliculus membrane. (2) The levels of portal endotoxin, but not proinflammatory cytokines, was increased. (3) Polymyxin B, but not the other antibiotics, prevented alterations in immunostaining for both 7H6 and mrp2, and cholestasis. We described that both hepatocyte TJs and the canalicular multispecific organic anion transporter were altered and that gut-derived endotoxin levels in the portal blood were increased in this rat colitis model.
Kawaguchi
T
T
Second Department of Medicine and Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan.
Sakisaka
S
S
Mitsuyama
K
K
Harada
M
M
Koga
H
H
Taniguchi
E
E
Sasatomi
K
K
Kimura
R
R
Ueno
T
T
Sawada
N
N
Mori
M
M
Sata
M
M
D000818:Animals; D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002779:Cholestasis / Q000473:pathology / Q000503:physiopathology*; D003092:Colitis / Q000378:metabolism* / Q000473:pathology*; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004731:Endotoxins / Q000097:blood; D015151:Immunoblotting; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011168:Portal System; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions / Q000502:physiology* / Q000648:ultrastructure; D062826:Zonula Occludens-1 Protein
D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D016207:Cytokines; D004731:Endotoxins; D008565:Membrane Proteins; D010750:Phosphoproteins; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; C089734:antigen 7H6