Effects of Inhaled Carbon Monoxide on Human Lung Inflammation

吸入一氧化碳对人体肺部炎症的影响

• 批准号: 8565323
• 负责人: ANTHONY F. SUFFREDINI
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8565323
• 关键词: Acute; Acute Respiratory Distress Syndrome; Adverse event; Age; Air; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Blinded; Breathing; Bronchoalveolar Lavage Fluid; Bronchoscopy; Carbon Monoxide; Cells; Data; Data Analyses; Development; Dose; Endotoxins; Enrollment; Ensure; Enzyme Activation; Exposure to; Female; Gases; Gene Expression; Heme; Hour; Human; Industrial Waste; Inflammation; Inflammation Mediators; Inflammatory Response; Intervention; Irrigation; Lung; Lung Inflammation; Masks; Metabolic; Modeling; Morbidity - disease rate; Oxygenases; Patients; Pattern; Physiological; Pilot Projects; Pneumonia; Predisposing Factor; Prevention strategy; Proteomics; Protocols documentation; Regimen; Role; Safety; Sampling; Sepsis; Staging; biological systems; healthy volunteer; high risk; male; mortality; prophylactic; randomized placebo controlled trial; response; volunteer

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.

急性呼吸窘迫综合征（ARDS）是发病率和死亡率的主要原因。在许多潜在的诱发因素中，败血症和肺炎代表了ARDS的两个主要原因。尽管近年来，ARDS患者的生存率增加，但仍估计约30％至40％。在这种情况下，发展ARD的高风险患者的有效预防策略至关重要。不幸的是，评估预防性ARDS的研究结果几乎令人失望。气态分子一氧化碳（CO）传统上被视为有毒的代谢和工业废物。但是，最近的研究表明，CO在许多生物系统中的重要生理作用。具体而言，在几种动物模型中已经证明了CO气体给药和血红素加氧酶激活（产生内源性CO气体的酶）的强抗炎，抗氧化剂和抗栓性作用。先前在我们部门进行的研究表明，在健康志愿者中，支气管镜滴注内毒素（LPS）会引起分室化的肺部炎症反应，这是一种出色的模型，可评估针对抑制肺部炎症的最早阶段的干预措施。 在当前单一盲，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后局部肺部炎症反应的影响。二十名健康的受试者，即18至40岁的男性或女性，将在6小时内通过口罩进行局部内毒素滴注，呼气CO或房间空气，然后在6小时内进行灌洗的重复支气管镜检查，以评估CO抑制肺部局部炎症的能力。 我们于2005年5月开始将受试者纳入试点研究，并于2005年10月完成了试点研究。试点研究招募了4名男性和4名女性。 我们分析了飞行员的数据，发现CO吸入良好的耐受性，并且没有导致任何不良事件。 另外，在这种低剂量下，没有证明CO吸入的显着抗炎作用。 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，内毒素的滴注和一氧化碳吸入良好，并且没有导致任何不良事件。 然而，尚未证明一氧化碳对内毒素诱导的炎症的显着抗炎作用。 该项目现已关闭以注册，并仅用于数据和样本分析。