Cell Stretch as a Physicochemical Secondary Stimulus in Initiating Lipopolysaccharide (LPS)-Mediated Acute Lung Injury

急性肺损伤(ALI)是由直接或间接损伤引起的一种通常是致命的疾病。当损伤直接发生时，例如肺炎，肺细胞会释放媒介，吸引参与防御身体的血细胞。一旦进入肺部，这些细胞就会被激活，吞噬或释放活性分子，摧毁入侵的有机体，这一过程称为炎症。当损伤间接发生时，例如败血症，ALI可能是由于体内其他部位产生的介质溢出而引起的。产生的活性分子会破坏将血液与空气隔开的肺屏障。结果，液体泄漏到空气空间，导致呼吸困难，阻碍气体交换。革兰氏(-)菌是败血症、肺炎和ALI的主要原因。炎症是由细菌细胞壁的主要成分--脂多糖(LPS)引发的。我们已经证明，内毒素还改变了呼吸以及肺内空气和血液的分布。这会在细胞伸展和空气中二氧化碳(CO2)的数量上产生局部变化。之前我们展示了细胞伸展会释放表面活性物质，这是一种使呼吸变得更容易的物质。我们现在假设细胞伸展是启动ALI的一个重要的次级刺激。我们将使用：1.分离的肺细胞来确定哪些细胞类型对内毒素的反应释放介质，以及是否：*拉伸刺激它们的释放*细胞类型之间的协调释放*释放受二氧化碳的量的影响。分离的肺来确定通风模式、血流和二氧化碳的量是否改变介质的释放，以及这些变化是否影响表面活性物质的分泌和使肺膨胀的能力。3.建立动物模型，以确定呼吸模式是否会改变呼吸衰竭的进程。了解导致这种疾病的机制将带来更好的治疗方法。

Acute lung injury (ALI) is an often fatal condition caused by direct or indirect injuries. When the injury occurs directly, eg pneumonia, lung cells release mediators that attract blood cells involved in defending the body. Once in the lungs, these cells are activated and engulf or release reactive molecules that destroy the invading organism a process known as inflammation. When the injury occurs indirectly, eg sepsis, ALI can arise from the spill-over of mediators created elsewhere in the body. Reactive molecules produced can damage the lung barrier separating the blood from the air. Consequently, fluid leaks into the airspaces making breathing difficult and hindering gas exchange. Gram (-) bacteria are the major cause of sepsis, pneumonia, and ALI. The inflammation is initiated by lipopolysaccharide (LPS), the major component of the bacterial cell wall. We have shown that LPS also changes breathing and the distribution of air and blood flow in lungs. This creates localised changes in cell stretch and the amounts of carbon dioxide (CO2) in the airspaces. Previously we showed that cell stretch releases surfactant , a substance that makes breathing easier. We now hypothesise that cell stretch is an important secondary stimulus in initiating ALI. We will use: 1. isolated lung cells to determine which cell types release mediators in response to LPS, and whether: * stretch stimulates their release * release is coordinated between the cell types * release is affected by the amount of CO2 2. isolated lungs to determine whether the pattern of ventilation, blood flow, and amounts of CO2 alter the release of the mediators, and whether these changes affect surfactant secretion and the ability to inflate the lungs. 3. animal models to also determine whether the pattern of respiration changes the course of the respiratory failure. Understanding the mechanisms that cause the disease will lead to better treatments.