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，脓毒症和肺炎是ARDS的两个主要原因。尽管近年来 ARDS 患者的生存率有所提高，但估计其死亡率仍约为 30% 至 40%。在这种背景下，针对ARDS高危患者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) 传统上被视为有毒的代谢废物和工业废物。然而，最近的研究表明二氧化碳在许多生物系统中具有重要的生理作用。具体而言，二氧化碳气体给药和血红素加氧酶激活（产生内源性二氧化碳气体的酶）具有强大的抗炎、抗氧化和抗血栓作用，已在多种动物模型中得到证实。我们科室之前进行的研究表明，健康志愿者经支气管镜滴注内毒素（LPS）会引起肺部炎症反应，这是评估早期抑制肺部炎症的干预措施的绝佳模型。 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给药后局部肺部炎症反应的影响。 20名年龄18至40岁的健康受试者，无论男性或女性，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小时时重复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。 我们于 2005 年 5 月开始招募受试者参加试点研究，并于 2005 年 10 月完成试点研究。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，发现二氧化碳吸入的耐受性良好，没有导致任何不良事件。 此外，在如此低的剂量下，吸入二氧化碳没有显着的抗炎作用。 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的耐受性良好，不会导致任何不良事件。 然而，一氧化碳对内毒素引起的炎症没有显着的抗炎作用。 该项目现已停止招生，仅开放用于数据和样本分析。