Pleural cavity as a driver of ventilator-induced systemic inflammation

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Mechanical ventilation is a crucial component of modern intensive care units. It allows operations to take place that would otherwise be impossible, and is an absolutely vital intervention for critically ill patients with respiratory failure, who would die without ventilator support. Ventilation is however not harmless, and it is now widely accepted that it can worsen patients' outcomes through a process called 'ventilator-induced lung injury', or VILI. People suffering from Acute Respiratory Distress Syndrome (ARDS), which can be caused by lung infections, sepsis, smoke inhalation and many other things, are at particularly high risk from VILI, although ventilation can cause damage even in people without underlying illness. Over the last 20 years, the only way doctors have found to reduce deaths among ARDS patients, is to reduce VILI. But mortality remains high (>40%) and it is likely that there is no way to ventilate without causing damage. Thus, understanding the mechanisms behind VILI is of crucial importance, especially given the huge numbers of critically ill patients currently being ventilated worldwide.The main problem seems to be that the body mounts an immune response to being ventilated, and the subsequent inflammation can cause damage to the lungs and other organs. To investigate this scientists have spent many years looking at different molecules and biological pathways, both inside the airspaces of the lung (alveoli) and within the blood. But these studies have not led to any treatments that work in patients.In this grant we have proposed an alternative idea, based on exploring the pleural cavity. The pleural cavity is a space between the lungs and the ribcage. It is known that this cavity fills with fluid in many ventilated patients, and that patients with more pleural fluid are sicker, but the reasons are not known. We believe that during VILI the pleural space becomes inflamed, and this then spreads around the rest of the body damaging different organs.We already have evidence to support this idea, but to prove it we will carry out various experiments in animal models (mainly mice) and in isolated cells. These will be designed to identify what types of cells and biological pathways are stimulated in the pleural space during ventilation, and how important this pleural cavity inflammation is by blocking different parts of the pathways we identify. If this hypothesis is correct, it has the potential to completely change the focus of investigations into VILI, and open up new avenues for the treatment of ventilated patients.