Metallothionein induction attenuates the progression of lung injury in mice exposed to long-term intermittent hypoxia.

Background: Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is prevalent in older adults and associated with inflammation. We previously showed that IH induces renal fibrosis and cardiomyopathy and hypothesized that lung inflammatory changes may underlie deficits in pulmonary function in OSA.

Methods: Pulmonary inflammatory and oxidative markers were assessed in metallothionein KO (MT-KO) mice and WT 129S1 controls exposed to IH or to normoxia for 8 weeks.

Results: MT expression increased at 3 days in WT, falling back at 1 week. Pro-fibrotic markers CTGF and PAI-1 were unchanged in WT, but increased at 3 or 8 weeks, with enhanced Sirius Red staining at 8 weeks, in IH-exposed MT-KO. Cellular infiltration, TNF-α and IL-6 increased earlier in IH-exposed MT-KO than in WT. Oxidative markers, 3-nitrotyrosine and 4-hydroxynonenal increased in both but persisted in MT-KO. Antioxidant Nrf2, HO-1 and NQO1, increased at 3 days in WT mice and at 8 weeks IH in MT-KO. While early Nrf2 induction required MT, its later increase at 8 weeks in MT-KO was independent from MT.

Conclusions: We conclude that early MT and antioxidant gene response protects from fibrotic changes in long-term IH-exposed mouse lung. Without this response, pulmonary fibrosis may develop with longer IH exposure.