Epidemiological investigations suggest that increased age is associated with susceptibility to infection. Pseudomonas aeruginosa (P. aeruginosa) infection and associated exotoxin A (PEA) toxicity have been reported in hospitalized elderly patients and young children with cystic fibrosis. The present study investigated age-related differences in PEA-induced hepatotoxicity in post weaning (PW, 3 weeks), young adult (YA, 12 weeks), and mature adult (MA, 60-64 weeks) rats. PEA (20 microg/kg) was injected intraveneously and mortality, clinical chemistry, hepatic histopathology, TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling) and PCNA (Proliferating cell nuclear antigen) staining, and serum cytokine levels were assessed at specific time points, up to 72 hr post-exposure (HPE). Mortality in MA rats was 100% at less than 48 HPE. Serum ALT levels in MA rats were approximately 5-fold greater than levels in PW and YA rats at 36 HPE. MA rat liver histological sections showed diffuse hepatocellular necrosis. In contrast, hepatocellular apoptosis, demonstrable by the TUNEL method, was noted simply in the periportal and midzonal regions from 36 to 48 HPE. Increased morphological mitoses and PCNA-positive hepatocytes were seen in PW and YA rats at 72 HPE. These parameters were correlated with age-dependent significant increases in TNF-alpha, IL-2, IL-6, and IL-18 levels. These data suggest that inflammatory cytokines play an important role in age-related differences in PEA-induced hepatotoxicity. Moreover, these cytokines might correlate with different patterns histopathologic features at various ages.