Proinflammatory cytokine deficiency and pathogenesis of Pseudomonas aeruginosa keratitis in aged mice

Corneal clarity in young adult Swiss (HSD:ICR) mice is restored after Pseudomonas aeruginosa infection. Previous data showed that this response involves a rapid up-regulation of constitutive intercellular cell adhesion molecule-1 (ICAM-1) and migration of inflammatory cells into the cornea. In contrast, in aged mice, there is no up-regulation of corneal ICAM-1 inflammatory cell infiltration into the cornea is delayed, and the cornea perforates. Therefore, the aim of this study was to test whether specific cytokines which up-regulate ICAM-1 expression differ in young and aged mice. Corneas of young (6- to 8-week-old) and aged (1- to 2-year-old) mice were scarified and inoculated with P. aeruginosa. The eyes were graded for pathologic changes (score 0 to +4); at 6, 12, 24, and 48 h postinfection (p.i.), six mite fi om each age group were sacrificed. Three corneas from each respective roup were excised for quantitation of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and gamma interferon (IFN-gamma) by enzyme-linked immunosorbent assay. The remaining three corneas from each age group were harvested for quantitation of viable bacteria by dir-ed plate count determination and for infiltrating polymorphonuclear leukocytes (PMNs) by a myeloperoxidase (MPO) assay. Compared to those of young mice, the corneas of infected aged mice had less IL-1 beta at 6 h p,i. (P less than or equal to 0.04) and less IFN-gamma at 12 to 48 h p.i. (P less than or equal to 0.05). Also, compared to those of young mice, corneas of aged mice had fewer PMNs (P less than or equal to 0.008) by the MPO assay at 6 h p.i. and more viable bacteria (P less than or equal to 0.01) per cornea by plate count determination at 23 h p.i. These data suggest that the lack of up-regulation of ocular ICAM-1 in aged mire may reflect a reduction in both IL-1 beta and IFN-gamma levels in the infected cornea. Consequently, a sufficient number of PMNs and other inflammation cells fail to rapidly migrate into the infected corneas of aged mice, the bacterial load is initially greater than that in young mice, and the cornea perforates.