title: Evidence for TIMP-1 protection against P. aeruginosa-induced corneal ulceration and perforation.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University-School of Medicine, Detroit, Michigan 48201, USA. kkernack@med.wayne.edu
authors.forename: K A
authors.initials: KA
authors.lastname: Kernacki
authors.forename: R
authors.initials: R
authors.lastname: Barrett
authors.forename: L D
authors.initials: LD
authors.lastname: Hazlett
mesh_terms: D000818:Animals; D003315:Cornea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003320:Corneal Ulcer / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D015818:Eye Infections, Bacterial / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D007074:Immunoglobulin G / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D011552:Pseudomonas Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000276:immunology; D012422:Rupture, Spontaneous / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000502:physiology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000502:physiology
chemical_list: D007074:Immunoglobulin G; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D009195:Peroxidase