Investigative ophthalmology & visual science · 1999
Evidence for TIMP-1 protection against P. aeruginosa-induced corneal ulceration and perforation.
СтатьяПоддержка исследования: вне правительства СШАПоддержка службы здравоохранения СШАНазвание и аннотация: Перевод пока не подготовлен
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Kernacki K A, Barrett R, Hazlett L D
Аннотация
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 these mice.
RESULTS: Greater amounts of TIMP-1 mRNA only were found in corneas of resistant versus suscep tible 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.
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 these mice.
RESULTS: Greater amounts of TIMP-1 mRNA only were found in corneas of resistant versus suscep tible 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.
Предметные рубрики MeSH
AnimalsCorneaCorneal UlcerEye Infections, BacterialImmunoglobulin GMiceMice, Inbred BALB CNeutrophilsPeroxidasePseudomonas InfectionsRNA, MessengerRabbitsRecombinant ProteinsRupture, SpontaneousTissue Inhibitor of Metalloproteinase-1Tissue Inhibitor of Metalloproteinase-2Tissue Inhibitor of Metalloproteinase-3