AM. Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury. Am J Physiol Lung Cell Mol Physiol 304: L350 -L360, 2013. First published December 28, 2012 doi:10.1152 doi:10. /ajplung.00243.2012 hepatic zinc accumulation at the expense of other organs, occurs in infection, inflammation, and aseptic lung injury. Mechanisms underlying zinc partitioning or its impact on extrahepatic organs are unclear. Here we show that the major zinc-binding protein, metallothionein (MT), is critical for zinc transmigration from lung to liver during hyperoxia and preservation of intrapulmonary zinc during hyperoxia is associated with an injury-resistant phenotype in MT-null mice. Particularly, lung-to-liver zinc ratios decreased in wild-type (WT) and increased significantly in MT-null mice breathing 95% oxygen for 72 h. Compared with female adult WT mice, MT-null mice were significantly protected against hyperoxic lung injury indicated by reduced inflammation and interstitial edema, fewer necrotic changes to distal airway epithelium, and sustained lung function at 72 h hyperoxia. Lungs of MT-null mice showed decreased levels of immunoreactive LC3, an autophagy marker, compared with WT mice. Analysis of superoxide dismutase (SOD) activity in the lungs revealed similar levels of manganese-SOD activity between strains under normoxia and hyperoxia. Lung extracellular SOD activity decreased significantly in both strains at 72 h of hyperoxia, although there was no difference between strains. Copper-zinc-SOD activity was ϳ4ϫ higher under normoxic conditions in MT-null compared with WT mice but was not affected in either group by hyperoxia. Collectively the data suggest that genetic deletion of MT-I/II in mice is associated with compensatory increase in copper-zinc-SOD activity, prevention of hyperoxia-induced zinc transmigration from lung to liver, and hyperoxia-resistant phenotype strongly associated with differences in zinc homeostasis during hyperoxic acute lung injury. zinc; metallothionein; hyperoxia; autophagy; CuZn-SOD; acute lung injury WHOLE BODY ZINC HOMEOSTASIS is efficiently controlled by a combination of absorption via gastrointestinal tract and excretion of this essential dietary micronutrient (26). This in turn is coupled to precise cellular and molecular control via coordinated activity of a large family of zinc importers, transporters, and the metal-binding protein metallothionein (MT) (13,31,35). In the presence of excess plasma zinc secondary to zinc infusion or exposure to dexamethasone or IL-6, metallothionein-mediated zinc transport into the liver occurs as a mechanism for maintaining zinc homeostasis (6). Hepatic zinc accumulation is particularly vital in inflammation and infection, supporting zinc-dependent acute phase reactions and host defense mechanisms, and MT is required for zinc accumulation in the livers of endotoxin-treated mice (47). Insight into the molecular mechanisms in the setting of sepsis (5) and liverdirected aseptic injury (e.g., turpentine) are evolving, and important ...