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

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Abstract

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.

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Funding

This study was supported in part by a University of Louisville Collaborative Matching Grant (to EG), 001GN09-Sleep Research Society Foundation/J. Christian Gillin M.D. (to JC).

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Author notes

  1. Guoguang Shao and Evelyne Gozal have equally contributed to this work

Authors and Affiliations

  1. Department of Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China

    Xingyu Lin & Guoguang Shao

  2. PRI, Departments of Pediatrics, University of Louisville, 570, S. Preston St., Ste 321, Louisville, 40202, USA

    Xingyu Lin, Rekha Jagadapillai, Jun Cai, Lu Cai & Evelyne Gozal

  3. Pharmacology and Toxicology, University of Louisville, Louisville, 40202, USA

    Lu Cai & Evelyne Gozal

  4. Physiology School of Medicine, University of Louisville, Louisville, 40202, USA

    Evelyne Gozal

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  1. Xingyu Lin
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  2. Rekha Jagadapillai
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  4. Lu Cai
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Correspondence to Guoguang Shao or Evelyne Gozal.

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Lin, X., Jagadapillai, R., Cai, J. et al. Metallothionein induction attenuates the progression of lung injury in mice exposed to long-term intermittent hypoxia. Inflamm. Res. 69, 15–26 (2020). https://doi.org/10.1007/s00011-019-01287-z

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  • DOI: https://doi.org/10.1007/s00011-019-01287-z

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