Zinc deficiency primes the lung for ventilator-induced injury
Francis Boudreault, … , Daniel J. Tschumperlin, Rebecca M. Baron
Francis Boudreault, … , Daniel J. Tschumperlin, Rebecca M. Baron
Published June 2, 2017
Citation Information: JCI Insight. 2017;2(11):e86507. https://doi.org/10.1172/jci.insight.86507.
View: Text | PDF
Research Article Inflammation Pulmonology

Zinc deficiency primes the lung for ventilator-induced injury

Abstract

Mechanical ventilation is necessary to support patients with acute lung injury, but also exacerbates injury through mechanical stress–activated signaling pathways. We show that stretch applied to cultured human cells, and to mouse lungs in vivo, induces robust expression of metallothionein, a potent antioxidant and cytoprotective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by high tidal volume mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc-binding transcription factor MTF1. We further show that mouse dietary zinc deficiency potentiates ventilator-induced lung injury, and that plasma zinc levels are significantly reduced in human patients who go on to develop acute respiratory distress syndrome (ARDS) compared with healthy and non-ARDS intensive care unit (ICU) controls, as well as with other ICU patients without ARDS. Taken together, our findings identify a potentially novel adaptive response of the lung to stretch and a critical role for zinc in defining the lung’s tolerance for mechanical ventilation. These results demonstrate that failure of stretch-adaptive responses play an important role in exacerbating mechanical ventilator–induced lung injury, and identify zinc and metallothionein as targets for lung-protective interventions in patients requiring mechanical ventilation.

Authors

Francis Boudreault, Miguel Pinilla-Vera, Joshua A. Englert, Alvin T. Kho, Colleen Isabelle, Antonio J. Arciniegas, Diana Barragan-Bradford, Carolina Quintana, Diana Amador-Munoz, Jiazhen Guan, Kyoung Moo Choi, MICU Registry, Lynette Sholl, Shelley Hurwitz, Daniel J. Tschumperlin, Rebecca M. Baron

×

Figure 5

Zinc deficiency promotes VILI and correlates with lower metallothionein (MT) lung protein levels.

Options: View larger image (or click on image) Download as PowerPoint
Zinc deficiency promotes VILI and correlates with lower metallothionein ...
(A) Zinc-deficient mice (n = 15) exhibited significantly increased physiologic dysfunction (increased elastance) compared with control mice (n = 7). *P < 0.05 versus control by 2-way repeated measures ANOVA after mechanical ventilation with modest tidal volumes (15 ml/kg tidal volume for 8 hours, percentage change from baseline) as well as with injurious tidal volumes (24 ml/kg for 8 hours) with a significant increase in elastance (B). *P < 0.05 by 2-way ANOVA with Bonferroni post-hoc test, n = 6 mice/control and 7 mice/zinc-deficient group; data presented as mean + SEM. (C) Lungs were harvested from mice subjected to ventilator-induced lung injury (VILI) as in panel B (n = 3–4/group) and pooled, and then harvested for protein and analyzed by Western blotting for MT or loading control (β-actin). (D–F) After 8 hours of mechanical ventilation with modest tidal volumes (mechanical ventilation 15 ml/kg), bronchoalveolar lavage (BAL) fluid was collected and analyzed for (D) total cell counts (baseline n = 6–9/ group, VILI n = 7–15 per group for both diets); (E) BAL total protein levels (baseline n = 6–7/ group, VILI n = 7–15/ group, for both diets), *P < 0.05 by 2-way ANOVA versus control diet 8-hour VILI, with Bonferroni post-hoc test; and (F) BAL IL-6 levels (baseline n = 6–7/group, VILI n = 5/group for both diets), *P < 0.05 by 2-way ANOVA, with Bonferroni post-hoc test versus control. All data are presented as mean + SEM. No difference in baseline levels for any of these outcomes was observed between to the 2 groups prior to mechanical ventilation.