Proton pump inhibitor induced collagen expression in colonocytes is associated with collagenous colitis.
OBJECTIVE
To elucidate the role of proton pump inhibitors (PPIs) in collagenous disease, direct effect of PPI on colonocytes was examined.


METHODS
Collagenous colitis is a common cause of non-bloody, watery diarrhea. Recently, there has been increasing focus on the use of proton PPIs as a risk factor for developing collagenous colitis. Mouse CT26 colonic cells were treated with PPI and/or PPI-induced alkaline media. Expression of fibrosis-associated genes was examined by RT-PCR. In human materials, collagen expression was examined by immunohistochemistry.


RESULTS
CT26 cells expressed a Na+-H+exchanger gene (solute carrier family 9, member A2). Treatment with PPI and/or PPI-induced alkaline media caused growth inhibition and oxidative stress in CT26 cells. The treatment increased expression of fibrosis inducing factors, transforming growth factor β and fibroblast growth factor 2. The treatment also decreased expression of a negative regulator of collagen production, replication factor C1, resulting in increased expression of collagen types III and IV in association with lipid peroxide. In biopsy specimens from patients with collagenous colitis, type III and IV collagen were increased. Increase of type III collagen was more pronounced in PPI-associated collagenous colitis than in non-PPI-associated disease.


CONCLUSIONS
From these findings, the reaction of colonocytes to PPI might participate in pathogenesis of collagenous colitis.
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan.
Shiori
S
Mori
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan.
Yui
Y
Kadochi
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan.
Yi
Y
Luo
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan.
Rina
R
Fujiwara-Tani
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan.
Yukiko
Y
Nishiguchi
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan.
Shingo
S
Kishi
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan.
Kiyomu
K
Fujii
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan.
Hitoshi
H
Ohmori
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan.
Hiroki
H
Kuniyasu
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002460:Cell Line; D046729:Colitis, Collagenous / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism*; D003106:Colon / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D008054:Lipid Peroxides / Q000737:chemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D018384:Oxidative Stress; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D008054:Lipid Peroxides; D054328:Proton Pump Inhibitors; C081517:SLC9A2 protein, human; D017923:Sodium-Hydrogen Exchangers; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D003094:Collagen
Collagenous colitis; Fibrosis; Oxidative stress; Proton pump inhibitor; pH