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)可在体外和某些肺部炎症动物模型中减少炎症反应。我们正在研究NO对人类局部肺部炎症的调节机制。有证据表明，在实验性肺部炎症中，NO可以调节炎症反应。一氧化氮供体在体外抑制人肺泡巨噬细胞炎性细胞因子的产生，防止IL-1诱导的中性粒细胞聚集和分离的大鼠肺水肿，并阻止败血症猪肺灌洗液中中性粒细胞、蛋白质和肺髓过氧化物酶含量的增加。只有有限的数据可用于吸入一氧化氮治疗急性肺损伤的人类。吸入NO 4d后，BAL患者BAL液中中性粒细胞自发过氧化氢生成、CD11b/CD18表达减少，IL-6、IL-8水平降低。一氧化氮仍在研究中，用于急性肺损伤的辅助治疗。我们正在评估NO改变与节段性内毒素滴注相关的炎症反应的能力。24名志愿者将以随机方式接受研究。最初的初步研究将在8名挑战支气管内毒素滴注的受试者中进行。在内毒素注射后，四名受试者将呼吸NO(40ppm)，由带储液袋的麻醉不再呼吸面罩传递，四名受试者将通过类似的面罩呼吸室内空气。受试者将通过循环呼吸6个小时。灌洗液细胞将通过细胞培养、功能研究、表面标志和细胞内细胞因子的流式细胞术以及mRNA的表达进行研究。将对灌洗液上清液进行各种炎性介质和炎性细胞激活标志物的评估。随后将采集血液样本进行白细胞总数和血浆炎症介质水平的检测。