Rapid PO2-changes as a mechanism of lung injury

Many critically-ill patients on an intensive care unit suffer from acute lung injury and require mechanical ventilation to support their failing lungs. However, mechanical ventilation is injurious in nature and can cause even further damage to the lungs. This ventilator-induced lung injury is highly relevant to intensive care therapy and has an impact on long-term consequences such as prolonged intensive care unit stay, reduced quality of life, cognitive impairment and disability. There is currently ongoing global investigation into the underlying mechanisms of injury, as well as into finding novel strategies for minimizing lung and distant organ injury caused by mechanical ventilation. One important mechanism of ventilator-induced lung injury is cyclic opening and closing of diseased lung areas. Recently, it could be demonstrated that in addition to mechanical forces, cyclic recruitment and derecruitment of lung areas also generates rapid partial pressure of oxygen (PO2-) changes in the lungs. The impact of these rapid PO2-changes on the lungs and other organs presently remains unknown. We hypothesize that rapid PO2-changes are an independent mechanism of lung injury. This proposal investigates for the first time in detail the underlying injurious mechanisms and involved signaling pathways surrounding rapid PO2-changes in the lungs. Firstly, using a novel cell culture model, we aim to study the effects of altered constant and rapidly changing PO2-levels on murine lung cell cultures, in order to analyze the key transcriptional responses caused by differing PO2-exposure at the cellular level. Further, the relative contributory role of different lung cell types and the effects of common anti-oxidant and anti-inflammatory agents will be tested. Subsequently, in order to translate our results from the cell culture level to an ex-vivo level, we will expose healthy pig lungs to the same constant and rapidly-changing PO2-levels using a novel ex-vivo lung perfusion model. This model combines high-frequency oscillation ventilation and extra-corporeal membrane oxygenation to produce precisely-targeted PO2-levels. Rapid PO2-changes can be generated by changing the lung ventilation or the lung perfusion all without applying any mechanical ventilator-related stress to the lungs. This innovative project will be conducted at the Department of Anesthesia, General Intensive Care and Pain Management at the Medical University of Vienna. With a special focus on mechanical ventilation/ARDS-related research, this institution is ideally equipped for studying rapid PO 2-changes as an additional mechanism of lung injury.

The mortality rate of patients with severe acute respiratory distress syndrome still hovers around 30-40%. Most patients do not die from initial respiratory failure but from secondary multi-organ failure. Therefore, novel causes of lung and remote organ injury are presently discussed. For example, cyclic rapid opening and closing of diseased lung areas cause rapid oxygen changes in the lungs, the systemic circulation and remote organs. In the present project, we hypothesize that rapid oxygen changes would represent a novel mechanism of lung injury. We have learned from our results that rapid oxygen changes induce molecular responses different from constant oxygen conditions and that this condition represents an independent mechanism of lung injury.