Effects of Inhaled Carbon Monoxide on Human Lung Inflammation

急性呼吸窘迫综合征(ARDS)是导致发病率和死亡率的主要原因。在许多潜在的诱因中，败血症和肺炎是ARDS的两个主要原因。尽管近年来存活率有所增加，但ARDS患者的死亡率估计仍在30%至40%左右。在这种背景下，在ARDS高危患者中制定有效的预防策略至关重要。不幸的是，评估ARDS预防方案的研究结果大多令人失望。气态分子一氧化碳(CO)传统上被认为是一种有毒的代谢和工业废物。然而，最近的研究表明，CO在许多生物系统中具有重要的生理作用。具体地说，在几种动物模型中，CO气体的应用和血红素加氧酶(产生内源性CO气体的酶)的激活都显示出强大的抗炎、抗氧化和抗血栓作用。我科以往的研究表明，在健康志愿者中，支气管镜下注入内毒素(LPS)可引起分区的肺部炎症反应，是评估早期抑制肺部炎症的干预措施的极佳模型。 在目前的单盲、随机、安慰剂对照研究中，我们评估了吸入一氧化碳对内毒素注射后局部肺部炎症反应的影响。20名健康受试者，男性或女性，年龄18~40岁，接受局部内毒素滴注，通过面罩呼吸CO或室内空气6小时，然后在6小时后再次进行支气管镜检查和灌洗，以评估CO抑制肺部局部炎症的能力。我们在2005年5月开始把受试者纳入先导研究，并于2005年10月完成先导研究。这项初步研究招募了4名男性和4名女性。我们分析了飞行员的数据，发现吸入CO的耐受性很好，没有导致任何不良事件。此外，在此低剂量下，CO吸入没有明显的抗炎作用。然后，我们在主要研究中招募了12名男性和12名女性。我们的主要研究结果表明，内毒素滴注和一氧化碳吸入耐受性良好，没有导致任何不良事件。然而，一氧化碳对内毒素诱导的炎症没有明显的抗炎作用。此项目现已关闭，仅供数据和样本分析使用。

Acute respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality. Of the many potential predisposing factors, sepsis and pneumonia represent the two main causes of ARDS. In spite of an increase in survival in recent years mortality in patients with ARDS is still estimated around 30 to 40%. In this context, development of effective preventive strategies in patients at high risk of development of ARDS is of paramount importance. Unfortunately, the results of studies evaluating prophylactic regimens for ARDS have been mostly disappointing. The gaseous molecule carbon monoxide (CO) has been traditionally viewed as a toxic metabolic and industrial waste. However, recent studies have demonstrated an important physiologic role of CO in many biological systems. Specifically, strong anti-inflammatory, anti-oxidant and anti-thrombotic effects of CO gas administration and heme oxygenase activation (the enzyme that generates endogenous CO gas) have been demonstrated in several animal models. Previous studies conducted in our department have demonstrated that bronchoscopic instillation of endotoxin (LPS) in healthy volunteers elicits a compartmentalized pulmonary inflammatory response, serving as an excellent model to evaluate interventions directed towards suppression of lung inflammation at its earliest stages. In the current single blinded, randomized, placebo controlled study, we evaluated the effects of inhaled carbon monoxide on local pulmonary inflammatory responses following endotoxin administration. Twenty healthy subjects, male or female, age 18 to 40 will undergo local endotoxin instillation, breath CO or room air through a mask for 6 hours, and then a repeat bronchoscopy with lavage will be done at 6 hours to assess the ability of CO to suppress local inflammation in the lung. We began enrolling subjects in May 2005 into the pilot study and completed the pilot study in October 2005. The pilot study enrolled 4 males and 4 females. We analyzed the data from the pilot and found the CO inhalation was well tolerated and did not result in any adverse events. In addition, at this low dose, no significant anti-inflammatory effects of CO inhalation were demonstrated. We then enrolled 12 males and 12 females in the main study. Our results from the main study demonstrate that Endotoxin instillation and Carbon Monoxide inhalation were well tolerated and did not result in any adverse events. However, no significant anti-inflammatory effects of Carbon Monoxide on Endotoxin induced inflammation were demonstrated. This project is now closed to enrollment and open for data and sample analysis only.