Targeting antioxidant gene expression to prevent and treat pulmonary redox imbalance in a murine model of ventilator-induced lung injury

• Applicant: Professor Dr. Roland Francis
• Subject Area: Anaesthesiology
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267695296

In this proposal, we introduce our previous work studying experimental strategies to attenuate oxidative stress in ventilator-induced lung injury.. These strategies include the potential anti-inflammatory effects of sulfide species, such as sodium sulfide solution (Na2S) and gaseous hydrogen sulfide (H2S). Our previous work in a mouse model of VILI has demonstrated that continuous inhalation of H2S gas enhances the expression of leukocyte adhesion and chemoattractant molecules in the lung, accelerates pulmonary edema formation, and promotes lung injury when it is inhaled at high concentrations (60 ppm) during mechanical ventilation with a high tidal volume. In contrast, we have demonstrated that systemic intravascular treatment with Na2S represent a novel therapeutic strategy to attenuate oxidative stress and to prevent VILI via antioxidative gene expression in this experimental model. Our work has substantiated both beneficial as well as detrimental effects of H2S and Na2S treatment. Therefore, in the current proposal, we aim to follow up on these studies by a) attempting to identify the underlying pulmonary and extrapulmonary mechanisms that mediate the protective effect of systemic Na2S treatment, and b) based on the know toxicology of inhaled H2S, will test alternative approaches which target similar antioxidative pathways, but with less toxicity. As a supplement, we propose to investigate aspects of lung-brain interaction to delineate and support new, innovative hypotheses related to the newly identified entity called ventilator-induced neurocognitive impairment (VINI). Preliminary results generated in this proposal (proof-of-principle) shall then set the stage for an independent follow-up proposal on VINI.

• DFG Programme: Research Grants