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(Investigative Ophthalmology and Visual Science. 2006;47:1500-1509.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-0361
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p38 Inhibitors Prevent TGF-ß–Induced Myofibroblast Transdifferentiation in Human Tenon Fibroblasts

Tobias Meyer-ter-Vehn,1,2 Susanne Gebhardt,2 Walter Sebald,2 Mathias Buttmann,3 Franz Grehn,1 Günther Schlunck,1,4 and Petra Knaus2,4,5

1From the Departments of Ophthalmology, 2Physiological Chemistry II, Biocenter, and 3Neurology, University of Würzburg, Würzburg, Germany; and 5Institute for Chemistry/Biochemistry, Free University Berlin, Berlin, Germany.

PURPOSE. The role of mitogen-activated protein kinase (MAPK) pathways in TGF-ß–induced myofibroblast transdifferentiation of human tenon fibroblasts (HTFs) was investigated to identify potential pharmacologic targets for the inhibition of scarring after glaucoma surgery.

METHODS. TGF-ß–dependent activation of Smad2, p38, and Erk-1/2 was examined by Western blot analysis. TGF-ß–induced mRNA expression of collagen I{alpha}1, fibronectin, and the myofibroblast transdifferentiation marker alpha smooth muscle actin ({alpha}-SMA) was analyzed by real-time RT-PCR. {alpha}-SMA protein expression and subcellular distribution were determined by Western blot analysis and immunofluorescence cytochemistry. Fibroblast contractility was assessed in three-dimensional collagen gel contraction assays, stress fiber assembly with rhodamine-phalloidin stains, and confocal microscopy. Cell proliferation was measured with an MTT assay. Specific pharmacologic kinase inhibitors were used to characterize the involvement of MAPK-dependent pathways.

RESULTS. TGF-ß stimulation of HTF induced a rapid and transient activation of Smad2 and Erk, whereas p38 activation was biphasic and sustained. After 24 hours of TGF-ß stimulation, increased levels of collagen I{alpha}1, fibronectin, and {alpha}-SMA transcripts were detected. After 3 days of stimulation, HTF displayed increased {alpha}-SMA protein levels, enhanced contractility, and assembly of actin stress fibers. TGF-ß also induced HTF proliferation. Specific p38 inhibitors prevented all these aspects of TGF-ß–induced myofibroblastic transdifferentiation.

CONCLUSIONS. Pharmacologic inhibition of p38 abrogates TGF-ß–induced myofibroblast transdifferentiation, reduces extracellular matrix protein expression and HTF proliferation, and may therefore serve to inhibit scarring after glaucoma surgery.




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