Thymosin-beta4 modulates corneal matrix metalloproteinase levels and polymorphonuclear cell infiltration after alkali injury.
OBJECTIVE
Corneal alkali injury is highly caustic, and present clinical therapies are limited. The purpose of this study was to investigate the ability of thymosin-beta4 (Taubeta4) to promote healing in an alkali injury model and the mechanisms involved in that process.


METHODS
Corneas of BALB/c mice were injured with NaOH, irrigated copiously with PBS, and treated topically with either Tbeta4 or PBS twice daily. At various time points after injury (PI), corneas from the Tbeta4- versus the PBS-treated group were examined for polymorphonuclear leukocyte (PMN) infiltration, chemokine, and matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) expression.


RESULTS
Tbeta4-treated corneas demonstrated improved corneal clarity at day 7 PI. Whereas Tbeta4 decreased corneal MMP-2 and -9 and MT6-MMP levels after alkali injury, no change in TIMP-1 and -2 expression was detected. Tbeta4 treatment also decreased corneal KC (CXCL1) and macrophage inflammatory protein (MIP)-2 chemokine expression and PMN infiltration. Immunohistochemistry studies demonstrated MMP-9 expression at the leading edge of the epithelial wound, in the the limbus (containing stem cells), and in stromal PMNs.


CONCLUSIONS
Tbeta4 treatment decreases corneal inflammation and modulates the MMP/TIMP balance and thereby promotes corneal wound repair and clarity after alkali injury. These results suggest that Tbeta4 may be useful clinically to treat severe inflammation-mediated corneal injuries.
Department of Ophthalmology, Kresge Eye Institute, Detroit, Michigan, 48201, USA. gsosne@med.wayne.edu
Gabriel
G
Sosne
Patricia L
PL
Christopherson
Ronald P
RP
Barrett
Rafael
R
Fridman
D000818:Animals; D002057:Burns, Chemical / Q000188:drug therapy* / Q000201:enzymology; D018925:Chemokines / Q000378:metabolism; D003316:Corneal Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005126:Eye Burns / Q000139:chemically induced*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012972:Sodium Hydroxide; D013947:Thymosin / Q000627:therapeutic use*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects; D000099201:Thymosin beta(4)
D018925:Chemokines; D020782:Matrix Metalloproteinases; D012972:Sodium Hydroxide; D013947:Thymosin; D019714:Tissue Inhibitor of Metalloproteinases; D000099201:Thymosin beta(4)