Targeting antioxidant gene expression to prevent and treat pulmonary redox imbalance in a murine model of ventilator-induced lung injury
Final Report Abstract
Ventilator-induced lung injury (VILI) is a serious complication of mechanical ventilation. A contributing factor to the pathophysiology of VILI is oxidative stress. A physiological protective response to oxidative stress is the activation of the Nrf2-ARE pathway. This induces Nrf2-dependent gene expression, ultimately increasing the production of antioxidant proteins to restore redox balance. Pharmacological activation of the Nrf2-ARE (antioxidative response element) pathway is possible with Nrf2 activators including sodium sulfide (Na2S), tertbutylhydroquinone (tBHQ) and epigallocatechin-3-gallate (EGCG). The main objective of this proposal was to explore in more detail the mechanism(s) by which Na 2S protects mice against ventilator-induced lung injury (VILI). Hence, we proposed to manipulate antioxidative signaling via pharmacological interventions to evaluate the therapeutic effectiveness of Nrf2 inducers/activators, such as tBHQ, EGCG, that activate the Nrf2-ARE signaling pathway. We asked whether targeted stimulation of antioxidative signaling represents a mechanism of protection against VILI. A mouse model of VILI using high tidal volume (HVT) ventilation to cause acute lung injury was used to answer this question. Prior to mechanical ventilation, mice were pretreated with tBHQ, EGCG, 3% ethanol (vehicle for tBHQ), slow-releasing sulfide donor GYY-4137 or phosphate buffered saline (controls). Survival, arterial blood oxygenation and respiratory system compliance were measured to assess functional outcome. Nrf2-dependent gene expression and antioxidant proteins (glutathione, NRF2) were used as surrogates to evaluate the activation the Nrf2-ARE pathway. This project demonstrates that the Nrf2-ARE pathway activator tBHQ improves survival and attenuates the development of pulmonary inflammation, lung edema, and respiratory system dysfunction of mice in a lethal one-hit model of VILI induced by mechanical ventilation with high tidal volumes. The protective effect of tBHQ is associated with increased pulmonary Nrf2-dependent antioxidant gene expression and can be considered an antioxidant preconditioning of the lung parenchyma. This project also demonstrates that Nrf2-dependent gene expression profiles vary with different Nrf2 activators (tBHQ, EGCG, GYY-4137), and this translates into different clinical outcomes (e.g. survival of VILI). These findings support the efficacy of pharmacological activation of the Nrf2-ARE pathway and of potential novel drug targets to increase the physiological resilience against oxidative stress responses during mechanical ventilation with risk of VILI. Several unexpected circumstances arose in the course of the project. These included model instability due to a change in the source of the experimental animals. Also unexpected was the sudden discontinuation of the distribution of one of the relevant study substances (Na2S). Finally, construction works in the experimental facility as well as the worldwide Sars-CoV2 pandemic resulted in significant restrictions of the research activities. All of these aspects contributed to a significant extension of the project duration. These unexpected circumstances were countered individually with an adequate alternative strategy. In this context, it is positive to mention that for this reason a new study substance was added (GYY-4137), the results of which (including RNA sequencing) have led us to new research aspects of the protective mechanisms in VILI. We plan to investigate these in the future. Our original research results were published in a top peer-review physiological journal, and were included in a PhD thesis of a young investigator. Two additional research proposals born of this project received positive approval and funding by the DFG. This will significantly help our group to continue elaborating on the mechanisms of VILI and organ interactions. Finally, the era of COVID-19 has brought to public attention the clinical relevance and urgent need for additional strategies to prevent VILI. This can save lives.
Publications
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Nrf2-antioxidant signalling pathway activator tBHQ protects mice against ventilator-induced lung injury. Hauptstadtkongress der DGAI, HAI 2018, 20.-22.09.2018, Berlin. Abstract: Anästh Intensivmed 20218;59:5573
Veskemaa L, Gonzalez-Lopez C, Pickerodt PA, Brandt B, Graw JA, Boemke W, Francis RCE
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Nrf2-antioxidant signalling pathway activator tBHQ protects mice against ventilator-induced lung injury. 5th International ARDS Conference, June 25-27, 2019, Berlin
Veskemaa L, Gonzalez-Lopez C, Pickerodt PA, Brandt B, Graw JA, Boemke W, Francis RCE
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Pharmacological activation of the Nrf2-ARE pathway and its protective effects in an experimental model of ventilator-induced lung injury. 17.09.2021
Veskemaa L
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Tert-butylhydroquinone augments Nrf2-dependent resilience against oxidative stress and improves survival of ventilator-induced lung injury in mice. Am J Physiol Lung Cell Mol Physiol. 2021 Jan 1;320(1):L17-L28
Veskemaa L, Graw JA, Pickerodt PA, Taher M, Boemke W, González-López A, Francis RCE
