Effects of combining selective PDE9 inhibition with inhaled nitric oxide on pulmonary gas exchange, mechanics, inflammation and lung injury in a murine model of ventilator induced lung injury.

• Applicant: Privatdozent Dr. Martin Wepler
• Subject Area: Anaesthesiology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 265345806

Acute respiratory distress syndrome (ARDS) is a severe, life-threatening reaction in adult patients to injuries or acute infections of the lung. Mechanical ventilation can be a life-saving therapy in terms of ARDS while providing adequate pulmonary gas exchange, but it can also have injurious effects on the lung tissue and thus worsening ARDS. The worsening of ARDS is caused by the pulmonary consequences of mechanical ventilation which have been termed ventilator-induced lung injury (VILI). Despite extensive developments of intensive care medicine VILI still contributes importantly to the mortality of ARDS. In patients with severe ARDS inhalation of nitric oxide (iNO) can have a potential benefit while improving systemic arterial oxygenation and mediating anti-inflammatory effects, but so far without altering survival rates. The effects of NO are mediated by the activation of an enzyme which produces the second messenger cyclic guanosine monophosphate (cGMP). Increased concentrations of cGMP are known to inhibit leukocyte adhesion and thus mediating the anti-inflammatory effects of NO. The action of cGMP is limited by phosphodiesterases (PDEs), enzymes which specifically hydrolyze cGMP. One PDE isoform, PDE9, is highly expressed in immune cells. From recent animal studies we learned, that the combination of a NO donor compound and the inhibition of PDE9 with BAY73-6691 showed a synergistic anti-inflammatory effect. To sum up, there are two critical questions to be addressed in this proposed study: 1) Is it possible to modulate cell properties of isolated neutrophil granulocytes with the combination of BAY73-6691 and NO donor compounds? 2) Does the combination of BAY73-6691 and iNO ameliorate inflammatory reactions and lung mechanics in a murine model of VILI which mimics the clinical facts of ARDS? In the first part of our study we will determine the in vitro effects of BAY 73-6691 alone and in combination with NO donor compounds on cGMP levels and cytokine production of murine neutrophils. In the second part of our study, we will examine the effects of BAY 73-6691 alone and in combination with iNO (5ppm) on inflammatory markers and lung compliance in a mouse model of VILI. Overall we expect to find higher survival rates in mice treated with BAY 73-6691 and iNO due to the proposed synergistic anti-inflammatory effect and beneficial impact on lung mechanics.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Warren Myron Zapol