Hypozincemia, with 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 ~4× 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.