Effects Of Inhaled Nitric Oxide On Pulmonary Inflammator

在体外和一些肺炎症动物模型中，吸入一氧化氮（NO）可减少炎症反应。我们正在研究一氧化氮调节人类局部肺部炎症的机制。有证据表明NO可以调节实验性肺炎症的炎症反应。一氧化氮供体体外抑制人肺泡巨噬细胞产生炎性细胞因子，阻止IL-1诱导的离体大鼠肺中性粒细胞积聚和水肿，并阻断脓毒猪肺灌洗中性粒细胞、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。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H2O2生成，CD11b/CD18表达减少，BAL液中IL-6和IL-8减少。一氧化氮作为急性肺损伤的辅助治疗仍在研究中。我们正在评估一氧化氮改变与节段性内毒素注入相关的炎症反应的能力。24名志愿者将以随机方式进行研究。最初的试点研究将在8名受试者中进行支气管内毒素注射。在内毒素注入后，4名受试者将通过带储气袋的麻醉无再呼吸面罩呼吸NO (40ppm)， 4名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、表面标记物和细胞内细胞因子流式细胞术以及mRNA表达来研究灌洗细胞。将对灌洗上清进行各种炎症介质和炎症细胞活化标记物的评估。连续的血液样本将获得总白细胞计数，以及炎症介质的血浆水平。

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.