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

急性肺损伤（ALI）是一种由直接或间接损伤引起的常见致死性疾病。当损伤直接发生时，如肺炎，肺细胞释放介质，吸引参与保卫身体的血细胞。一旦进入肺部，这些细胞被激活并吞噬或释放反应分子，摧毁入侵的生物体，这一过程称为炎症。当损伤间接发生时，如败血症，ALI可由体内其他部位产生的介质溢出引起。产生的活性分子会破坏将血液与空气分离的肺屏障。因此，流体泄漏到空气空间中，使得呼吸困难并阻碍气体交换。革兰氏阴性菌是败血症、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。我们已经表明，LPS也改变呼吸和肺中空气和血液流动的分布。这会导致细胞伸展和空气中二氧化碳（CO2）量的局部变化。之前我们展示了细胞拉伸释放表面活性剂，一种使呼吸更容易的物质。我们现在假设细胞牵张是引发ALI的一个重要的次级刺激。我们将使用：用途：1.分离的肺细胞，以确定哪些细胞类型释放介质响应LPS，以及是否：* 拉伸刺激它们的释放 * 释放是协调细胞类型之间 * 释放受CO2 2量的影响。分离的肺，以确定是否通气模式，血流和CO2的量改变介质的释放，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.动物模型，以确定呼吸模式是否改变呼吸衰竭的过程。了解导致疾病的机制将导致更好的治疗。

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.