PPARalpha ligand WY14643 reduced acute rejection after rat lung transplantation with the upregulation of IL-4, IL-10 and TGFbeta mRNA expression.
BACKGROUND
The peroxisome proliferators-activated receptor-alpha (PPARalpha) is important in lipid metabolism and regulation of inflammation. Recent studies have demonstrated the immunoregulatory effects of PPARalpha. This investigated the immunosuppressive effects of PPARalpha using its ligand, WY14643, on acute lung allograft rejection in a rat model and its mechanism of action.


METHODS
The left lungs were transplanted orthotopically from Brown-Norway donors to F344 recipients. The recipients were then divided into control and WY14643 treatment groups. The allograft rejection was evaluated by daily chest X-ray imaging and was evaluated histologically on Day 7 after transplantation. The cytokine messenger RNA (mRNA) expression at Days 3 and 5 were also evaluated in allografts and recipient spleens.


RESULTS
The radiologic and histologic findings indicated that treatment with the WY14643 reduced acute allograft rejection. WY14643 also significantly extended the allograft survival time. This amelioration of acute rejection by WY14643 was also associated with up-regulated interleukin (IL)-4, IL-10, and transforming growth factor-beta (TGFbeta) mRNA expression in the lung allografts and spleens.


CONCLUSIONS
This study demonstrated that the administration of the PPARa ligand, WY14643, ameliorates acute lung allograft rejection in rats. Treatment with WY14643 reduced histopathologic scores, prolonged graft survival, and up-regulated the expression of anti-inflammatory cytokine IL-4, IL-10, and TGFbeta mRNA compared with the control.
Yanagisawa
Jun
J
Department of Thoracic Surgery and Department of Biochemistry, Fukuoka University School of Medicine, Fukuoka, Japan. platinum13jp@yahoo.co.jp
Shiraishi
Takeshi
T
Iwasaki
Akinori
A
Maekawa
Shinichi
S
Higuchi
Takao
T
Hiratuka
Masafumi
M
Tanaka
Toshihiro
T
Shibaguchi
Hirotomo
H
Kuroki
Masahide
M
Shirakusa
Takayuki
T
D000818:Animals; D006084:Graft Rejection / Q000473:pathology* / Q000517:prevention & control*; D016753:Interleukin-10 / Q000235:genetics*; D015847:Interleukin-4 / Q000235:genetics*; D016040:Lung Transplantation / Q000473:pathology*; D047493:PPAR alpha / Q000502:physiology*; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000235:genetics*; D015854:Up-Regulation
D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; C006253:pirinixic acid