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Karen A. Kernacki, Ronald Barrett, Linda D. Hazlett; Evidence for TIMP-1 Protection Against P. aeruginosa–Induced Corneal Ulceration and Perforation. Invest. Ophthalmol. Vis. Sci. 1999;40(13):3168-3176.
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purpose. To determine the biological significance of individual endogenous
tissue inhibitors of metalloproteinases (TIMPs) in protection against
tissue destruction using a Pseudomonas
aeruginosa–induced model of corneal ulceration.
methods. Corneal TIMP-1, -2, and -3 mRNA levels were compared between young
adult (resistant) and aged (susceptible) mice challenged with P.
aeruginosa. Resistant mice that demonstrated greater amounts of
an individual TIMP were treated with polyclonal antibody (pAb) to that
TIMP. To determine whether TIMP neutralization exacerbated P.
aeruginosa–induced corneal disease, TIMP pAb– and normal
rabbit serum (NRS)- (control) treated mice were examined
macroscopically and histopathologically after infection. Corneal
neutrophil (PMN) myeloperoxidase (MPO) levels also were examined in
results. Greater amounts of TIMP-1 mRNA only were found in corneas of resistant
versus susceptible mice after P. aeruginosa challenge.
Systemic treatment of resistant mice with TIMP-1 pAb resulted in
corneal perforation by 5 to 7 days after infection (PI).
Histopathologic evaluation of corneal tissues from TIMP-1 pAb– versus
NRS-treated mice confirmed that TIMP-1 pAb treatment resulted in
extensive stromal dissolution. This treatment also was associated with
loss of epithelium within the central cornea. Both the histopathology
and PMN MPO enzyme assays also showed an increase in corneal PMN number
following TIMP-1 pAb treatment.
conclusions. These studies provide evidence that, after P. aeruginosa infection, adequate endogenous expression of TIMP-1 in cornea protects
against extensive corneal tissue destruction. The protective effects of
TIMP-1 may be multifactorial. In addition to directly protecting
extracellular matrix components from active matrix metalloproteinases,
TIMP-1 may either directly or indirectly influence recruitment of PMNs
into infected cornea. Finally, TIMP-1 also may affect wound healing and
resurfacing of the corneal epithelium.
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