Effects of Inhaled Carbon Monoxide on Human Lung Inflammation

急性呼吸窘迫综合征（ARDS）是导致发病和死亡的主要原因。在许多潜在的诱发因素中，脓毒症和肺炎代表了ARDS的两个主要原因。尽管近年来生存率有所提高，但ARDS患者的死亡率估计仍在30%至40%左右。在这种情况下，发展有效的预防策略，在高风险的患者发展的ARDS是至关重要的。不幸的是，评估ARDS预防方案的研究结果大多令人失望。气体分子一氧化碳（CO）传统上被视为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。具体而言，CO气体给药和血红素加氧酶激活（产生内源性CO气体的酶）的强烈抗炎、抗氧化和抗血栓形成作用已在几种动物模型中得到证实。在我们部门进行的先前研究已经证明，在健康志愿者中支气管镜滴注内毒素（LPS）可引起肺间质炎症反应，可作为评价针对在最早阶段抑制肺部炎症的干预措施的良好模型。 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给药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至40岁）将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小时时进行重复支气管镜检查和灌洗，以评估CO抑制肺部局部炎症的能力。 我们于2005年5月开始招募受试者进入试点研究，并于2005年10月完成试点研究。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CO吸入耐受性良好，未导致任何不良事件。 此外，在该低剂量下，未证实CO吸入的显著抗炎作用。 然后，我们在主研究中招募了12名男性和12名女性。 我们的主研究结果表明，内毒素滴注和一氧化碳吸入耐受性良好，未导致任何不良事件。 然而，一氧化碳对内毒素诱导的炎症没有显著的抗炎作用。 该项目现已停止招募，仅开放用于数据和样本分析。

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.