Grant: Project Grant

Mechanical ventilation (MV) is indispensable for the survival of critically ill patients, such as those with respiratory failure. However, improperly delivered, can aggravate or cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). ATP (adenosine triphosphate) is a universal source of energy (fuel) in all living cells. ATP can be also released outside the cell, where it serves as a signaling molecule for cell-to-cell communication. However, high levels of extracellular ATP act as danger-associated signal leading to lung inflammation, edema and tissue damage. Such detrimental effects of ATP are implicated in a number of respiratory diseases including ventilator induced lung injury (VILI), ALI and ARDS and involve binding of ATP to specific proteins (called receptors) on the surface of neighboring cells. One of such ATP receptor, designated as P2X7, is specifically implicated in pathogenesis of VILI. However, the mechanisms of massive ATP release that activate P2X7 during lung mechanical ventilation remain unknown. Interventions that would reduce excessive release of ATP would benefit patients with ALI/ARDS. We hypothesize that massive ATP release results from rupture of cell membranes (cell lysis) due to excessive mechanical stress during MV. In this project we will study the impact of MV on lung injury using in vivo and ex vivo mice lungs. We will also use recently developed by our team a novel bioluminescence microscopy to visualize in real-time injury-induced ATP release in ex vivo lungs. We will test pharmacological interventions (ATP metabolizing enzymes and inhibitors of ATP receptor P2X7) to reduce excessive ATP release and its downstream detrimental effects. This project will help to understand pathogenesis of ALI/ARDS - major critical care pulmonary complications. It will facilitate design of novel strategies to mitigate or prevent these pathologies.