Effects Of Inhaled Nitric Oxide On Pulmonary Inflammator

吸入一氧化氮对肺部炎症的影响

• 批准号: 6683784
• 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/6683784
• 关键词: chemical structure function; cytokine; drug screening /evaluation; endotoxins; flow cytometry; human subject; human therapy evaluation; immunomodulators; inflammation; inhalation drug administration; lung injury; lung lavage; nitric oxide; patient oriented research; respiratory disorder chemotherapy

Inhaled nitric oxide (NO) diminishes inflammatory responses in vitro and in some animal models of lung inflammation. We are studying the mechanisms involved in NO modulation of local pulmonary inflammation in humans. Evidence suggest that NO can modulate the inflammatory response in experimental lung inflammation. Nitric oxide donors inhibit inflammatory cytokine production by human alveolar macrophages in vitro, prevents IL-1 induced neutrophil accumulation and edema in isolated rat lungs, and blocked increases in pulmonary lavage neutrophils, protein, and lung myeloperoxidase content in septic swine. Only limited data are available in humans treated with inhaled nitric oxide for acute lung injury. After 4 days of inhaled NO, patients had a reduction of BAL neutrophil spontaneous H2O2 production, CD11b/CD18 expression, and less IL-6 and IL-8 in BAL fluid compared to patients who did not receive inhaled NO. Nitric oxide remains under investigation for adjunctive therapy for acute lung injury. We are evaluating the ability of NO to alter the inflammatory response associated with segmental endotoxin instillation. Twenty-four volunteers will be studied in a randomized fashion. An initial pilot study will be performed in eight subjects challenged with bronchial endotoxin instillation. Following the endotoxin instillation, four subjects will breathe NO (40 ppm), delivered by an anesthesia non-rebreathing face mask with a reservoir bag and four subjects will breathe room air through a similar mask. The subjects will breathe through the circuit for 6 hours. The lavage cells will be studied using cell culture, functional studies, surface markers and intracellular cytokines with flow cytometry, and mRNA expression. The lavage supernatant will be evaluated for various inflammatory mediators and markers of inflammatory cell activation. Sequential blood samples will be obtained for total leukocyte counts, as well as plasma levels of inflammatory mediators.

吸入一氧化氮（NO）减少了体外炎症反应，并且在某些肺部炎症模型中会减少炎症反应。我们正在研究不调节人类局部肺部炎症的机制。证据表明，没有可以调节实验性肺部炎症中的炎症反应。一氧化氧化物的供体在体外抑制人肺泡巨噬细胞的炎症细胞因子的产生，IL-1可防止孤立的大鼠肺中嗜中性粒细胞的积累和水肿，并阻止肺泡中粒细胞，蛋白质和肺骨髓氧化酶含量增加。仅在用吸入一氧化氮治疗的急性肺损伤的人类中才能获得有限的数据。吸入4天后，与未接受吸入的患者相比，BAL液中BAL中性粒细胞自发性H2O2产生，CD11b/CD18表达以及BAL液中的IL-6和IL-8的减少。一氧化氮仍在研究急性肺损伤的辅助治疗。我们正在评估NO改变与分段内毒素滴注相关的炎症反应的能力。将以随机的方式研究二十四名志愿者。最初的试点研究将在受支气管内毒素滴注挑战的八个受试者中进行。在内毒素滴注之后，由麻醉的非呼吸面膜带有储层袋和四个受试者将通过类似的口罩呼吸空气的四个受试者（40 ppm），这是由麻醉的非呼吸面罩发出的。受试者将通过电路呼吸6小时。灌洗细胞将使用流式细胞术和mRNA表达的细胞培养，功能研究，表面标记和细胞内细胞因子进行研究。将评估灌洗上清液的各种炎症介质和炎症细胞激活的标志物。将获得总白细胞计数以及血浆炎症介质水平的顺序血液样本。