Investigation of the effects of intravenous fluid therapy and Imatinib administration in a human intravenous lipopolysaccharide (LPS) model of sepsis.

问题：脓毒症是一种常见的，失控的免疫反应感染，往往导致人们成为危重病，并需要入院重症监护。脓毒症是世界范围内的主要死亡原因。红细胞通过小血管将氧气输送到全身。脓毒症导致通过血管的血流变得异常，使得某些区域可能无法接收足够的血流，因此没有足够的氧气。没有氧气，体内细胞停止工作并死亡，导致重要器官，如肾脏和心脏衰竭。最终，这种器官衰竭导致严重疾病和死亡。脓毒症也会对形成血管内层的特殊细胞（称为内皮细胞）造成损害。结果，血管变得“渗漏”，允许液体从血管移动到周围区域。这种泄漏的液体导致血管周围区域肿胀，使氧气更难到达需要氧气的细胞。脓毒症的一个关键治疗方法是静脉注射液体，即直接进入静脉，以改善身体周围的血液流动。然而，有证据表明，过多的液体可能是有害的，甚至可能使脓毒症患者更容易死亡。给予液体可能会对血管内壁造成更大的损伤，从而使肿胀恶化。这种额外的肿胀使得氧气更难输送到需要的地方，导致多个器官衰竭。显然，确定静脉输液对脓毒症患者血管和血流的影响非常重要，因为它可能有助于或造成伤害。研究方案：我们将通过静脉注射给健康志愿者一种从细菌中提取的物质，称为脂多糖（LPS），然后将这种物质注射到静脉中。几十年来，LPS已安全可靠地给予数百人。它会导致一个可预测的和非常温和的脓毒症样状态几个小时，类似于一个温和的流感。症状可以用扑热息痛治疗，尽管这通常不是必需的。接受LPS治疗的患者可在24小时或更短时间内完全康复。这将在设备齐全的医学研究中心进行，并配备训练有素的重症监护医生。我们将使用一个专门的相机，让我们看到舌头下的小血管。我们将在给予LPS之前和之后24小时内测量血流量并观察血管。我们也会每隔一段时间抽取血液样本，观察接受LPS后的免疫反应。在给予LPS后，一些志愿者会接受静脉输液，而另一些则不会。通过比较两组，我们可以看到静脉注射液体对血液流动、小血管和免疫系统的影响。除了静脉输液，我们还计划研究一种名为伊马替尼的药物的效果，伊马替尼是一种非常安全的药物，用于治疗一种白血病已有数十年的历史。许多研究表明，伊马替尼也可能有助于保护内皮细胞免受损伤。有些志愿者将给予伊马替尼，有些则不会。再次，通过比较血液流量，血管和免疫反应的血液标志物，我们将能够看到伊马替尼是否有任何有益的效果。应用和好处：通过这项研究，我们希望建立对小血管和免疫系统的影响，通过给予LPS健康的人类志愿者，以产生轻微的脓毒症样状态。我们还旨在了解静脉输液和伊马替尼治疗对这种败血症样疾病患者的影响。我们的研究结果将帮助我们设计未来的临床试验，看看是否不同的方式给予液体，或伊马替尼，可以帮助真实的世界脓毒症患者。该项目将导致更好地治疗败血症。

The problem:Sepsis is a common, out-of-control immune response to infection which often causes people to become critically ill and require admission to intensive care. Sepsis is a leading cause of death world-wide. Red blood cells carry oxygen around the body through small blood vessels. Sepsis causes blood flow through the blood vessels to become abnormal, so that some areas may not receive enough blood flow and hence not enough oxygen. Without oxygen, cells in the body stop working and die, causing vital organs, such as the kidneys and heart, to fail. Ultimately, this organ failure leads to critical illness and death. Sepsis also causes damage to special cells, called endothelial cells, which form the inner lining of blood vessels. As a result, the blood vessels become "leaky", allowing fluid to move from the blood vessels into surrounding areas. This leaked fluid causes swelling of the areas surrounding the blood vessels, making it even harder for oxygen to reach the cells where it is needed. A key treatment for sepsis is to give fluids intravenously, that is directly into a vein, in order improve blood flow around the body. However, there is evidence that too much fluid may be harmful, perhaps even making patients with sepsis more likely to die. Giving fluid may cause more damage to the lining of blood vessels, thereby making swelling worse. This additional swelling makes it even more difficult for oxygen to be delivered to where it is required, resulting in the failure of multiple organs. It is clearly very important to establish the effects of intravenous fluid on blood vessels and blood flow in people with sepsis, as it may be either helping or causing harm. It is also important to find out if any drugs can protect the blood vessels from damage in the first place or control the immune response to infection.The Research Proposal: We will give healthy volunteers a substance derived from bacteria, known as lipopolysaccharide (LPS), by injection into a vein. LPS has been safely and reliably given to hundreds of people over several decades. It causes a predictable and very mild sepsis-like state for a few hours, similar to a mild flu. Symptoms can be treated with Paracetamol, although this is usually not required. People who are given LPS recover fully within 24 hours or less. This will be carried out in a fully equipped medical research centre with trained intensive care doctors. We will use a specialised camera that will allow us to see the small blood vessels under the tongue. We will measure blood flow and look at blood vessels before and up to 24 hours after giving LPS. We will also take blood samples at intervals to look at the immune response to receiving LPS.After giving LPS, some volunteers will be given intravenous fluids, and some not. By comparing the two groups, we can see what effect, if any, intravenous fluid has on blood flow, on small blood vessels and on the immune system. As well as intravenous fluids, we also plan to investigate the effect of a drug called imatinib, a very safe drug used for decades to treat a type of leukaemia. A number of studies have shown that imatinib may also help protect endothelial cells from damage. Some of the volunteers will be given imatinib and some will not. Again, by comparing the blood flow, blood vessels and blood markers of the immune response, we will be able to see if imatinib has any beneficial effects.Applications and Benefits:Through this study, we hope to establish the effects on small blood vessels and on the immune system by giving LPS to healthy human volunteers in order to produce a mild sepsis-like state. We also aim to understand the effects of intravenous fluid and imatinib treatment in people with this sepsis-like condition. Our findings will help us to design future clinical trials to see if different ways of giving fluid, or imatinib, can help real world patients with sepsis. This project will lead to better treatment of sepsis.