Zinc deficiency primes the lung for ventilator-induced injury

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; Lynette Sholl; Shelley Hurwitz; Daniel J Tschumperlin; Rebecca M Baron; MICU Registry

doi:10.1172/jci.insight.86507

Zinc deficiency primes the lung for ventilator-induced injury

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, Lynette Sholl, Shelley Hurwitz, Daniel J Tschumperlin, Rebecca M Baron, MICU Registry

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42 Citas (Scopus)

Resumen

La ventilación mecánica es necesaria para apoyar a los pacientes con lesión pulmonar aguda, pero también exacerba la lesión a través de las vías de señalización activadas por estrés mecánico. Demostramos que el estiramiento aplicado a las células humanas cultivadas, y a los pulmones de los ratones in vivo, induce la expresión robusta de la metalothioneína, una potente molécula antioxidante y citoprotectora crítica para la homeostasis celular del zinc. Además, la deficiencia genética de los genes de la metalotionina murina exacerbó la lesión pulmonar causada por la ventilación mecánica de alto volumen tidal, identificando un papel adaptativo para estos genes en la limitación de la lesión pulmonar. La inducción del estiramiento de la metalothioneína requería zinc y el factor de transcripción de unión del zinc MTF1. Además, se muestra que la deficiencia de zinc en la dieta de los ratones potencia la lesión pulmonar inducida por el ventilador y que los niveles de zinc en plasma se reducen significativamente en los pacientes humanos que desarrollan el síndrome de dificultad respiratoria aguda (SDRA) en comparación con los controles de las unidades de cuidados intensivos (UCI) sanas y no sanas (UCI), así como con otros pacientes de la UCI sin SDRA. En conjunto, nuestros hallazgos identifican una respuesta adaptativa potencialmente novedosa del pulmón al estiramiento y un papel crítico para el zinc en la definición de la tolerancia del pulmón a la ventilación mecánica. Estos resultados demuestran que el fracaso de las respuestas de adaptación al estiramiento juega un papel importante en la exacerbación de la lesión pulmonar inducida por el ventilador mecánico, e identifican el cinc y la metalotioneína como dianas para las intervenciones de protección pulmonar en pacientes que requieren ventilación mecánica.

Idioma original	Inglés estadounidense
Publicación	JCI insight
Volumen	2
N.º	11
DOI	https://doi.org/10.1172/jci.insight.86507
Estado	Publicada - jun. 2 2017
Publicado de forma externa	Sí

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Boudreault, F., Pinilla-Vera, M., Englert, J. A., Kho, A. T., Isabelle, C., Arciniegas, A. J., Barragan-Bradford, D., Quintana, C., Amador-Munoz, D., Guan, J., Choi, K. M., Sholl, L., Hurwitz, S., Tschumperlin, D. J., Baron, R. M., & MICU Registry (2017). Zinc deficiency primes the lung for ventilator-induced injury. JCI insight, 2(11). https://doi.org/10.1172/jci.insight.86507

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title = "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.",

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

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T1 - Zinc deficiency primes the lung for ventilator-induced injury

AU - Boudreault, Francis

AU - Pinilla-Vera, Miguel

AU - Englert, Joshua A

AU - Kho, Alvin T

AU - Isabelle, Colleen

AU - Arciniegas, Antonio J

AU - Barragan-Bradford, Diana

AU - Quintana, Carolina

AU - Amador-Munoz, Diana

AU - Guan, Jiazhen

AU - Choi, Kyoung Moo

AU - Sholl, Lynette

AU - Hurwitz, Shelley

AU - Tschumperlin, Daniel J

AU - Baron, Rebecca M

AU - MICU Registry

PY - 2017/6/2

Y1 - 2017/6/2

N2 - 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.

AB - 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.

U2 - 10.1172/jci.insight.86507

DO - 10.1172/jci.insight.86507

M3 - Article

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SN - 2379-3708

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JO - JCI insight

JF - JCI insight

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ER -

Zinc deficiency primes the lung for ventilator-induced injury

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