Pleural cavity as a driver of ventilator-induced systemic inflammation

机械通气是现代重症监护病房的重要组成部分。它允许进行原本不可能进行的手术，对于呼吸衰竭的危重患者来说，这绝对是一种至关重要的干预措施，如果没有呼吸机支持，这些患者将会死亡。然而，通气并不是无害的，现在人们普遍认为，它可以通过称为“呼吸机诱发的肺损伤”（VILI）的过程使患者的预后恶化。患有急性呼吸窘迫综合征（ARDS）的人患VILI的风险特别高，这种疾病可能由肺部感染、败血症、烟雾吸入和许多其他事情引起，尽管通气即使对没有潜在疾病的人也会造成损害。在过去的20年里，医生们发现减少ARDS患者死亡的唯一方法就是减少VILI。但死亡率仍然很高（约40%），而且很可能没有办法在不造成损害的情况下进行通风。因此，了解VILI背后的机制至关重要，特别是考虑到目前世界范围内大量危重患者正在接受通气治疗。主要问题似乎是身体对通风产生免疫反应，随后的炎症会对肺部和其他器官造成损害。为了研究这个问题，科学家们花了许多年的时间研究不同的分子和生物途径，既在肺（肺泡）的空气中，也在血液中。但这些研究还没有找到任何对病人有效的治疗方法。在这项研究中，我们提出了另一种基于胸膜腔的方法。胸膜腔是肺和胸腔之间的空隙。众所周知，在许多通气患者中，该腔充满液体，胸膜积液较多的患者病情较重，但原因尚不清楚。我们认为，在VILI期间，胸膜空间会发炎，然后扩散到身体的其他部位，损害不同的器官。我们已经有证据支持这一观点，但为了证明这一点，我们将在动物模型（主要是小鼠）和分离细胞中进行各种实验。这些将被设计用来确定在通气过程中胸膜腔中刺激了哪些类型的细胞和生物途径，以及通过阻断我们确定的途径的不同部分，胸膜腔炎症有多重要。如果这一假设是正确的，它有可能彻底改变对VILI的研究重点，并为通气患者的治疗开辟新的途径。

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.