title: Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Wakayama Medical University, Kimiidera, Wakayama 641-0012, Japan. shizuya@wakayama-med.ac.jp
authors.forename: Shizuya
authors.initials: S
authors.lastname: Saika
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamanaka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Flanders
authors.forename: Jiyun
authors.initials: J
authors.lastname: Yoo
authors.forename: Anita B
authors.initials: AB
authors.lastname: Roberts
authors.forename: Iku
authors.initials: I
authors.lastname: Nishikawa-Ishida
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ohnishi
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Muragaki
authors.forename: Akira
authors.initials: A
authors.lastname: Ooshima
mesh_terms: 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
chemical_list: 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