Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells.
Proliferative vitreoretinopathy (PVR) is one of the major causes of the failure of retinal detachment surgery. Its pathogenesis includes a fibrotic reaction by the retinal pigment epithelium and other retina-derived non-neural cells, leading to fixation of the detached retina. We examined the role of p38 mitogen-activated protein kinase (MAPK) in transforming growth factor (TGF)-beta2-dependent enhancement of the fibrogenic reaction in a human retinal pigment epithelial cell line, ARPE-19, and also evaluated the therapeutic efficacy of inhibiting p38MAPK by adenoviral gene transfer of dominant-negative (DN) p38MAPK in a mouse model of PVR. Exogenous TGF-beta2 activates p38MAPK in ARPE-19 cells. It also suppresses cell proliferation, but this was unaffected by addition of the p38MAPK inhibitor, SB202190. SB202190 interfered with TGF-beta2-dependent cell migration and production of collagen type I and fibronectin, but had no effect on basal levels of these activities. While SB202190 did not affect phosphorylation of the C-terminus of Smads2/3, it did suppress the transcriptional activity of Smads3/4 as indicated by a reporter gene, CAGA12-Luc. Gene transfer of DN-p38MAPK attenuated the post-retinal detachment fibrotic reaction of the retinal pigment epithelium in vivo in mice, supporting its effectiveness in preventing/treating PVR.
Saika
Shizuya
S
Department of Ophthalmology, Wakayama Medical University, Kimiidera, Wakayama 641-0012, Japan. shizuya@wakayama-med.ac.jp
Yamanaka
Osamu
O
Ikeda
Kazuo
K
Kim-Mitsuyama
Shokei
S
Flanders
Kathleen C
KC
Yoo
Jiyun
J
Roberts
Anita B
AB
Nishikawa-Ishida
Iku
I
Ohnishi
Yoshitaka
Y
Muragaki
Yasuteru
Y
Ooshima
Akira
A
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015316:Genetic Therapy; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010857:Pigment Epithelium of Eye / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053781:Transforming Growth Factor beta2; D018630:Vitreoretinopathy, Proliferative / Q000235:genetics / Q000473:pathology / Q000628:therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
D024042:Collagen Type I; D004791:Enzyme Inhibitors; D005353:Fibronectins; D007093:Imidazoles; D011725:Pyridines; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole