| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
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
1, fibronectin, and the myofibroblast transdifferentiation marker alpha smooth muscle actin (-SMA) was analyzed by real-time RT-PCR. -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 I1, fibronectin, and -SMA transcripts were detected. After 3 days of stimulation, HTF displayed increased -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.
This article has been cited by other articles:
|
|
 |
|
  M.-P. Wu, M.-J. Young, C.-C. Tzeng, C.-R. Tzeng, K.-F. Huang, L.-W. Wu, and C.-Y. Chou A novel role of thrombospondin-1 in cervical carcinogenesis: inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer Carcinogenesis, June 1, 2008; 29(6): 1115 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Honjo, H. Tanihara, T. Kameda, T. Kawaji, N. Yoshimura, and M. Araie Potential Role of Rho-Associated Protein Kinase Inhibitor Y-27632 in Glaucoma Filtration Surgery Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5549 - 5557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Y. Ma, G. H. Tesch, R. A. Flavell, R. J. Davis, and D. J. Nikolic-Paterson MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1556 - F1563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ebihara, S. Yamagami, L. Chen, T. Tokura, M. Iwatsu, H. Ushio, and A. Murakami Expression and Function of Toll-like Receptor-3 and -9 in Human Corneal Myofibroblasts Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 3069 - 3076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Meyer-ter-Vehn, S. Sieprath, B. Katzenberger, S. Gebhardt, F. Grehn, and G. Schlunck Contractility as a Prerequisite for TGF-{beta}-Induced Myofibroblast Transdifferentiation in Human Tenon Fibroblasts Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 4895 - 4904. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
