Therapeutic effect of topical administration of SN50, an inhibitor of nuclear factor-kappaB, in treatment of corneal alkali burns in mice.
We evaluated the therapeutic efficacy of topical administration of SN50, an inhibitor of nuclear factor-kappaB, in a corneal alkali burn model in mice. An alkali burn was produced with 1 N NaOH in the cornea of C57BL/6 mice under general anesthesia. SN50 (10 microg/microl) or vehicle was topically administered daily for up to 12 days. The eyes were processed for histological or immunohistochemical examination after bromodeoxyuridine labeling or for semi-quantification of cytokine mRNA. Topical SN50 suppressed nuclear factor-kappaB activation in local cells and reduced the incidence of epithelial defects/ulceration in healing corneas. Myofibroblast generation, macrophage invasion, activity of matrix metalloproteinases, basement membrane destruction, and expression of cytokines were all decreased in treated corneas compared with controls. To elucidate the role of tumor necrosis factor (TNF)-alpha in epithelial cell proliferation, we performed organ culture of mouse eyes with TNF-alpha, SN50, or an inhibitor of c-Jun N-terminal kinase (JNK) and examined cell proliferation in healing corneal epithelium in TNF-alpha-/- mice treated with SN50. An acceleration of epithelial cell proliferation by SN50 treatment was found to depend on TNF-alpha/JNK signaling. In conclusion, topical application of SN50 is effective in treating corneal alkali burns in mice.
Saika
Shizuya
S
Department of Ophthalmology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-0012, Japan. shizuya@wakayama-med.ac.jp
Miyamoto
Takeshi
T
Yamanaka
Osamu
O
Kato
Tadashi
T
Ohnishi
Yoshitaka
Y
Flanders
Kathleen C
KC
Ikeda
Kazuo
K
Nakajima
Yuji
Y
Kao
Winston W-Y
WW
Sato
Misako
M
Muragaki
Yasuteru
Y
Ooshima
Akira
A
D000287:Administration, Topical; D000468:Alkalies; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002057:Burns, Chemical / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003315:Cornea / Q000473:pathology / Q000503:physiopathology; D065306:Corneal Injuries; D003319:Corneal Stroma / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005126:Eye Burns / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005347:Fibroblasts / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage* / Q000627:therapeutic use; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing
D000468:Alkalies; D016207:Cytokines; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D045726:Metalloproteases