Zusammenfassung
Die Vernarbung des operativ geschaffenen Kammerwasserabflusswegs ist das Hauptproblem der filtrierenden Glaukomchirurgie. Zytostatika können die Vernarbung hemmen, doch schränken unerwünschte Wirkungen ihren Einsatz ein. In dieser Übersicht werden Mechanismen und Besonderheiten der Wundheilung nach filtrierenden Glaukomoperationen erörtert und neuere Entwicklungen im Bereich der Wundheilungsmodulation vorgestellt. Der Wachstumsfaktor TGF-β spielt eine zentrale Rolle in der Wundheilung und Narbenbildung, weshalb ein Abfangen von TGF-β und die spezifische Blockade nachgeschalteter intrazellulärer Signale eine verbesserte Wundheilungsmodulation ermöglichen können. Zahlreiche neue Substanzklassen befinden sich in der präklinischen Erprobung und begründen die Hoffnung auf verbesserte Behandlungsmethoden durch eine erweiterte postoperative Kombinationstherapie.
Abstract
Conjunctival scarring remains the major problem in filtering glaucoma surgery. Antimetabolites afford a reduction of scar formation, but considerable side effects limit their application. Here, we review the mechanisms and peculiarities of wound healing following glaucoma surgery and report on new developments in the field of wound healing modulation. The growth factor TGF-β has a central role in wound healing and scarring. Therefore, novel concepts of wound healing modulation comprise scavenging of TGF-β and specific inhibition of disinct downstream intracellular signalling pathways. Several compounds have entered preclinical evaluation and offer new potential to modulate scarring in future combination therapies.
Schlüsselwörter
Glaukom - Wundheilung - TGF-beta
Key words
glaucoma - wound healing - TGF-beta
Literatur
-
1
The Advanced Glaucoma Intervention Study (AGIS) .
7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators.
Am J Ophthalmol.
2000;
130 (4)
429-440
-
2
Batterbury M, Wishart P K.
Is high initial aqueous outflow of benefit in trabeculectomy?.
Eye.
1993;
7 (Pt 1)
109-112
-
3
Baudouin C. et al .
Efficacy of indomethacin 0.1 % and fluorometholone 0.1 % on conjunctival inflammation following chronic application of antiglaucomatous drugs.
Graefes Arch Clin Exp Ophthalmol.
2002;
240 (11)
929-935
-
4
Broadway D C. et al .
Reversal of topical antiglaucoma medication effects on the conjunctiva.
Arch Ophthalmol.
1996;
114 (3)
262-267
-
5
Chang L. et al .
The role of the immune system in conjunctival wound healing after glaucoma surgery.
Surv Ophthalmol.
2000;
45 (1)
49-68
-
6
Chen H S. et al .
Control of filtering bleb structure through tissue bioengineering: An animal model.
Invest Ophthalmol Vis Sci.
2006;
47 (12)
5310-4
-
7
Chicurel M E, Chen C S, Ingber D E.
Cellular control lies in the balance of forces.
Curr Opin Cell Biol.
1998;
10 (2)
232-239
-
8
Cordeiro M F.
Beyond Mitomycin: TGF-beta and wound healing.
Prog Retin Eye Res.
2002;
21 (1)
75-89
-
9
Cordeiro M F, Gay J A, Khaw P T.
Human anti-transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent.
Invest Ophthalmol Vis Sci.
1999;
40 (10)
2225-2234
-
10
Cordeiro M F. et al .
Novel antisense oligonucleotides targeting TGF-beta inhibit in vivo scarring and improve surgical outcome.
Gene Ther.
2003;
10 (1)
59-71
-
11
Eibl K H. et al .
Alkylphosphocholines: a new therapeutic option in glaucoma filtration surgery.
Invest Ophthalmol Vis Sci.
2004;
45 (8)
2619-2624
-
12
Eming S A. et al .
Accelerated wound closure in mice deficient for interleukin-10.
Am J Pathol.
2007;
170 (1)
188-202
-
13
Ferguson M W, O’Kane S.
Scar-free healing: from embryonic mechanisms to adult therapeutic intervention.
Philos Trans R Soc Lond B Biol Sci.
2004;
359 (1445)
839-850
-
14
Gabbiani G.
The myofibroblast in wound healing and fibrocontractive diseases.
J Pathol.
2003;
200 (4)
500-503
-
15
Grehn F.
Chirurgie des primären Offenwinkelglaukoms.
Klin Monatsbl Augenheilkd.
2008;
225 (1)
30-38
-
16
Grehn F. et al .
Factors affecting the outcome of trabeculectomy: an analysis based on combined data from two phase III studies of an antibody to transforming growth factor beta2, CAT-152.
Ophthalmology.
2007;
114 (10)
1831-1838
-
17
Grisanti S. et al .
Decorin modulates wound healing in experimental glaucoma filtration surgery: a pilot study.
Invest Ophthalmol Vis Sci.
2005;
46 (1)
191-196
-
18
Honjo M. et al .
Potential role of Rho-associated protein kinase inhibitor Y-27 632 in glaucoma filtration surgery.
Invest Ophthalmol Vis Sci.
2007;
48 (12)
5549-5557
-
19
Jendrossek V. et al .
Intracellular mediators of erucylphosphocholine-induced apoptosis.
Oncogene.
2003;
22 (17)
2621-2631
-
20
Khaw P. et al .
A phase III study of subconjunctival human anti-transforming growth factor beta(2) monoclonal antibody (CAT-152) to prevent scarring after first-time trabeculectomy.
Ophthalmology.
2007;
114 (10)
1822-1830
-
21
Klink T. et al .
Nachsorge nach filtrierenden Glaukomoperationen.
Ophthalmologe.
2006;
103 (9)
815-823
-
22
Klink T, Schrey S, Elsesser U. et al .
Interobserver variability of the Wuerzburg bleb classification score.
Ophthalmologica.
2008;
222
im Druck
-
23
Kumar S, Boehm J, Lee J C.
p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases.
Nat Rev Drug Discov.
2003;
2 (9)
717-726
-
24
Lee J C. et al .
p38 mitogen-activated protein kinase inhibitors – mechanisms and therapeutic potentials.
Pharmacol Ther.
1999;
82 (2 – 3)
389-397
-
25
Marquardt D, Lieb W E, Grehn F.
Intensified postoperative care versus conventional follow-up: a retrospective long-term analysis of 177 trabeculectomies.
Graefes Arch Clin Exp Ophthalmol.
2004;
242 (2)
106-113
-
26
Martin P. et al .
Wound healing in the PU.1 null mouse – tissue repair is not dependent on inflammatory cells.
Curr Biol.
2003;
13 (13)
1122-1128
-
27
Mead A L. et al .
Evaluation of anti-TGF-beta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery.
Invest Ophthalmol Vis Sci.
2003;
44 (8)
3394-3401
-
28
Meyer-ter-Vehn T. et al .
P38 inhibitors prevent TGF-b-induced myofibroblast transdifferentiation in human tenon fibroblasts.
Invest Ophthalmol Vis Sci.
2006;
47
1500-1509
-
29
Meyer-ter-Vehn T, Grehn F, Schlunck G.
Localization of TGF-beta type II receptor and ED-A fibronectin in normal conjunctiva and feiled filtering blebs.
Mol Vis.
2008;
14
136-141
-
30
Meyer-ter-Vehn T. et al .
Contractility as a prerequisite for TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts.
Invest Ophthalmol Vis Sci.
2006;
47 (11)
4895-4904
-
31
Mietz H, Jacobi P C, Krieglstein G K.
Intraoperative episcleral versus postoperative topical application of mitomycin-C for trabeculectomies.
Ophthalmology.
2002;
109 (7)
1343-1349
-
32
Mietz H, Krieglstein G K.
Postoperative application of mitomycin c improves the complete success rate of primary trabeculectomy: a prospective, randomized trial.
Graefes Arch Clin Exp Ophthalmol.
2006;
244 (11)
1429-1436
-
33
Ng C P, Hinz B, Swartz M A.
Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro.
J Cell Sci.
2005;
118 (Pt 20)
4731-4739
-
34
Pasquale L R. et al .
Immunolocalization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 in the anterior segment of the human eye.
Invest Ophthalmol Vis Sci.
1993;
34 (1)
23-30
-
35
Peters T. et al .
Wound-healing defect of CD 18(–/–) mice due to a decrease in TGF-beta1 and myofibroblast differentiation.
Embo J.
2005;
24 (19)
3400-3410
-
36
Picht G, Grehn F.
Development of the filtering bleb after trabeculectomy. Classification, histopathology, wound healing process.
Ophthalmologe.
1998;
95 (5)
W380-W387
-
37
Picht G. et al .
Transforming growth factor beta 2 levels in the aqueous humor in different types of glaucoma and the relation to filtering bleb development.
Graefes Arch Clin Exp Ophthalmol.
2001;
239 (3)
199-207
-
38
Schenk S, Quaranta V.
Tales from the crypt[ic] sites of the extracellular matrix.
Trends Cell Biol.
2003;
13 (7)
366-375
-
39
Serini G. et al .
The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1.
J Cell Biol.
1998;
142 (3)
873-881
-
40
Shah M, Foreman D M, Ferguson M W.
Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta.
Lancet.
1992;
339 (8787)
213-214
-
41
Shah M, Foreman D M, Ferguson M W.
Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring.
J Cell Sci.
1995;
108 (Pt 3)
985-1002
-
42
Shaunak S. et al .
Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation.
Nat Biotechnol.
2004;
22 (8)
977-984
-
43
Siriwardena D. et al .
Human antitransforming growth factor beta(2) monoclonal antibody – a new modulator of wound healing in trabeculectomy: a randomized placebo controlled clinical study.
Ophthalmology.
2002;
109 (3)
427-431
-
44
Tomasek J J. et al .
Myofibroblasts and mechano-regulation of connective tissue remodelling.
Nat Rev Mol Cell Biol.
2002;
3 (5)
349-363
-
45
Tripathi R C. et al .
Trabecular cells of the eye express messenger RNA for transforming growth factor-beta 1 and secrete this cytokine.
Invest Ophthalmol Vis Sci.
1993;
34 (8)
2562-2569
-
46
Tripathi R C. et al .
Aqueous humor in glaucomatous eyes contains an increased level of TGF-beta 2.
Exp Eye Res.
1994;
59 (6)
723-727
-
47
Tura A. et al .
The Rho-kinase inhibitor H-1152P suppresses the wound-healing activities of human Tenon’s capsule fibroblasts in vitro.
Invest Ophthalmol Vis Sci.
2007;
48 (5)
2152-2161
-
48
Wong T T, Mead A L, Khaw P T.
Prolonged antiscarring effects of ilomastat and MMC after experimental glaucoma filtration surgery.
Invest Ophthalmol Vis Sci.
2005;
46 (6)
2018-2022
-
49
Wong T T. et al .
Matrix metalloproteinases in disease and repair processes in the anterior segment.
Surv Ophthalmol.
2002;
47 (3)
239-256
-
50
Yamanaka O. et al .
Inhibition of p38 MAP kinase suppresses fibrogenic reaction in conjunctiva in mice.
Mol Vis.
2007;
13
1730-1739
Dr. Günther Schlunck
Augenklinik und Poliklinik Universität Würzburg
Josef-Schneider-Str. 11
97080 Würzburg
Telefon: ++ 49/9 31/20 12 03 51
Fax: ++ 49/9 31/20 12 04 90
eMail: schlunck_g@klinik.uni-wuerzburg.de
