The application proposes to generate knockout mutants for the two heme oxgenase isozymes, HO-1 and HO-2, and to examine the effect of these mutations on response to oxidative stress. The hypothesis to be tested is that contributes to cellular protection against oxidative stress- induced injury and adaptation to repeated oxidative stress exposures. The specific aims of this proposal are: 1) Targeting disruption, by homologous recombination, of either or both HO-1 and HO-2 genes and examine the phenotypes of the mutated mice. 2) Characterize the response of HO-1 and HO-2 and double knockout mice to oxidative injury by ozone in vivo, and by 4-hydroxynonenal (HNE) and H202 in vitro. The response will be examined with respect to cell injury (apoptosis necrosis, inflammation, and formation of HNE protein adducts. 3) Generate mice with the most important response elements of the HO-1 gene (distal 5' AP-1 sites) mutated. 4) And, examine the response of mice with mutated AP-1 sites to oxidative injury by ozone in vivo, and ability to adapt to repeated ozone exposures.