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: 6825004
• 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/6825004
• 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. Following the endotoxin instillation, subjects will breathe NO (40 ppm), delivered by an anesthesia non-rebreathing face mask with a reservoir bag and control 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）在体外和一些肺部炎症的动物模型中减少炎症反应。我们正在研究NO调节人类局部肺部炎症的机制。有证据表明，NO可以调节实验性肺部炎症的炎症反应。一氧化氮供体在体外抑制人肺泡巨噬细胞产生炎性细胞因子，防止IL-1诱导的中性粒细胞在离体大鼠肺中的积聚和水肿，并阻断脓毒症猪肺灌洗液中性粒细胞、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人类吸入一氧化氮治疗急性肺损伤。吸入NO 4天后，与未吸入NO的患者相比，患者BAL中性粒细胞自发H2 O2产生、CD 11b/CD 18表达减少，BAL液中IL-6和IL-8减少。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。将以随机方式对24名志愿者进行研究。内毒素滴注后，受试者将呼吸NO（40 ppm），通过带有储液袋的麻醉非再呼吸面罩输送，对照受试者将通过类似的面罩呼吸室内空气。受试者将通过回路呼吸6小时。将使用细胞培养、功能研究、表面标志物和细胞内细胞因子（流式细胞术）以及mRNA表达研究灌洗细胞。将评价灌洗液上清液中的各种炎症介质和炎症细胞活化标志物。将连续采集血液样本，用于总白细胞计数以及炎症介质的血浆水平。