In vivo studies with gene-deleted mouse strains have provided much information on the roles of HO-1 and HO-2 in oxygen tolerance. Dennery et al. demonstrated that heme oxygenase-2 knockout mice (ho-2 -/-) were more sensitive to the lethal effects of hyperoxia than wild-type mice [116] . In addition to the absence of HO-2 expression, however, the mice displayed a compensatory increase in HO-1 protein expression, and higher total lung HO activity. Thus, in this model, the combination of HO-2 deletion and HO-1 overexpression resulted in a hyperoxiasensitive phenotype. Recent studies of Dennery et al. have shown that HO-1-deleted (ho-1 -/-) mice were more resistant to the lethal effects of hyperoxia than the corresponding wild type [117] . The hyperoxia resistance observed in the ho-1 -/strain could be reversed by the reintroduction of HO-1 by adenoviral-mediated gene transfer [117] . In contrast, mouse embryo fibroblasts derived from ho-1 -/mice showed increased sensitivity to the toxic effects of hemin and H 2 O 2 and generated more intracellular reactive oxygen species in response to these agents [118] . Both ho-1 -/-and ho-2 -/strains were anemic, yet displayed abnormal accumulations of tissue iron. Specifically, ho-1 -/accumulated nonheme iron in the kidney and liver and had decreased total iron content in the lung, while ho-2 -/mice accumulated total lung iron in the absence of a compensatory increase in ferritin levels [116, 119] . The mechanism(s) by which HO-1 or HO-2 deletions result in accumulation of tissue iron remain unclear. These studies, taken together, have indicated that animals deficient in either HO-1 and HO-2 display altered sensitivity to oxidative stress conditions. Aberrations in the distribution of intra-and extra-cellular iron, may underlie in part, the differential sensitivity observed [116, 117] .