Expression of Smad7 in mouse eyes accelerates healing of corneal tissue after exposure to alkali.
Damage to the cornea from chemical burns is a serious clinical problem that often leads to permanent visual impairment. Because transforming growth factor (TGF)-beta has been implicated in the response to corneal injury, we evaluated the effects of altered TGF-beta signaling in a corneal alkali burn model using mice treated topically with an adenovirus (Ad) expressing inhibitory Smad7 and mice with a targeted deletion of the TGF-beta/activin signaling mediator Smad3. Expression of exogenous Smad7 in burned corneal tissue resulted in reduced activation of Smad signaling and nuclear factor-kappaB signaling via RelA/p65. Resurfacing of the burned cornea by conjunctival epithelium and its differentiation to cornea-like epithelium were both accelerated in Smad7-Ad-treated corneas with suppressed stromal ulceration, opacification, and neovascularization 20 days after injury. Introduction of the Smad7 gene suppressed invasion of monocytes/macrophages and expression of monocyte/macrophage chemotactic protein-1, TGF-beta1, TGF-beta2, vascular endothelial growth factor, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-2 and abolished the generation of myofibroblasts. Although acceleration of healing of the burned cornea was also observed in mice lacking Smad3, the effects on epithelial and stromal healing were less pronounced than those in corneas treated with Smad7. Together these data suggest that overexpression of Smad7 may have effects beyond those of simply blocking Smad3/TGF-beta signaling and may represent an effective new strategy for treatment of ocular burns.
Saika
Shizuya
S
Department of Ophthalmology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-0012, Japan. shizuya@wakayama-med.ac.jp
Ikeda
Kazuo
K
Yamanaka
Osamu
O
Miyamoto
Takeshi
T
Ohnishi
Yoshitaka
Y
Sato
Misako
M
Muragaki
Yasuteru
Y
Ooshima
Akira
A
Nakajima
Yuji
Y
Kao
Winston W-Y
WW
Flanders
Kathleen C
KC
Roberts
Anita B
AB
D000256:Adenoviridae / Q000235:genetics; D000468:Alkalies; D000818:Animals; D002057:Burns, Chemical / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division; D003315:Cornea / Q000473:pathology / Q000503:physiopathology; D065306:Corneal Injuries; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005123:Eye / Q000378:metabolism / Q000503:physiopathology*; D005126:Eye Burns / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006133:Growth Substances / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein; D051906:Smad7 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*
D000468:Alkalies; D004268:DNA-Binding Proteins; D006133:Growth Substances; D016328:NF-kappa B; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators