Bronchoalveolar macrophages (MΦ) are directly exposed to the toxic effects of hyperoxia. One of many adverse effects of hyperoxia is the oxidization of metal groups in proteins (e.g., zinc-fingers). We postulated that “leaky” metals, most notably zinc, could induce the expression of the following cytoprotective, early genes in MΦ: metallothionein (MT), heme oxygenase (HO) and early growth response-1(egr-1). It is known that these genes are induced by oxidative stresses such as hydrogen peroxide, ionizing radiation, and endotoxin exposure. Furthermore, we speculate that nitric oxide (NO) would inhibit the expression of these genes. These hypotheses were tested using two clones of a rat alveolar macrophage cell line (NR8383) which spontaneously produced over a 24 hour period either high (5.5 μM) or low (<0.5 μM) concentrations of nitrite, an end-product of NO synthesis. Using Northern blot analyses and rodent probes, we showed that 100 μM zinc chloride significantly induced mRNA expression for MT, HO, and egr-1 in the low nitrite-producing cells, while the high nitrite-generating clone had substantially reduced expression of mRNA for these three cytoprotective proteins. Overnight pre-incubation of the high NO-producing clone with the competitive NO synthase inhibitor, N-monomethyl-L-arginine (final concentration =1mM), resulted in significant MT, HO, and egr-1 mRNA expression after Zn treatment. Alternatively, pre-incubation of the low NO-producing MΦ clone with S-nitroso-N-acetylpenicillamine (final concentration= 0.5 mM), a NO donor, caused ≥50% reduction in MT, HO and egr-1 mRNA expression after Zn exposure. We conclude that 100 μM Zn (normal plasma contains 10 μM zinc) upregulates the expression of MT, HO and egr-1 mRNA in rat alveolar macrophages and that NO can reduce this induction. We speculate that hypertoxia-related release of Zn from proteins may provide a mechanism whereby macrophages and other lung cells induce secondary oxidant stress genes. Furthermore, the inhibition of MT, HO and egr-1 induction by NO raises a question whether clinically-relevant concentrations of inhaled NO during oxygen therapy may adversely influence cellular responses to oxidative stress.