Controlled Photo-Release of Nitric Oxide for Antimicrobial Inhalation Therapy

用于抗菌吸入疗法的一氧化氮的受控光释放

• 批准号: 9298198
• 负责人: STEVEN P. SCHWENDEMAN
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298198
• 关键词: Adult; Adult Respiratory Distress Syndrome; Adverse effects; Affect; Air; Antiviral Agents; Bacteria; Biomass; Blood; Breathing; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical; Cystic Fibrosis; Disease; Dose; Encapsulated; Epithelial Cells; Failure; Floods; Formulation; Frequencies; Gases; Geometry; Glass; Goals; Home environment; Hospitals; Human; Humidifier; In Vitro; Incubated; Individual; Infection; Inhalation Therapy; Intensive Care; Light; Lighting; Link; Liquid substance; Lower Respiratory Tract Infection; Lung; Lung Transplantation; Medical; Medicine; Membrane; Methods; Microbial Biofilms; Monitor; Mutation; N-acetylpenicillamine; Neonatology; Nitric Oxide; Nitric Oxide Donors; Orphan Drugs; Oxygenators; Patients; Phase; Platelet Activation; Plexiglass; Pneumonia; Polymers; Population; Procedures; Pulmonary Hypertension; Research; Respiratory Tract Infections; Risk; S-nitro-N-acetylpenicillamine; Sepsis Syndrome; Side; Signal Transduction; Silicone Elastomers; Sinus; Sinusitis; Source; Staphylococcus aureus; Stream; Surface; System; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Tube; Vasodilator Agents; antimicrobial; base; chronic rhinosinusitis; cost; cystic fibrosis patients; high risk; in-home care; inhaled nitric oxide; interest; killings; natural antimicrobial; neonatal pulmonary hypertension; new technology; novel strategies; outcome forecast; portability; prevent; sensor; treatment duration

Nitric oxide (NO) is a potent and endogenous antimicrobial/antiviral agent normally present at moderate levels (200-1000 ppbv) within the upper airways/sinuses of healthy patients, helping to prevent chronic upper airway infections. Patients suffering from chronic rhinosinusitis (CRS) and other conditions with difficult-to-treat lower respiratory infections—chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and others—could potentially benefit from home treatment with inhaled NO therapy (iNO). While iNO at much higher levels (10- 50 ppmv) is used routinely in hospitals for neonatal pulmonary hypertension and adult acute respiratory distress syndrome, the extremely high cost of current iNO systems ($3,000 per day) precludes their use for home treatment of respiratory tract infections associated with CRS, COPD and CF. For such disorders, administration of doses of NO that mimic levels normally found in the upper airways of healthy individuals could be a safe and effective method of preventing or treating upper and lower respiratory infection. Herein, we propose to study a new low-cost delivery strategy to generate pure nitric oxide (NO) for iNO therapy, which could be used in the hospital or at home for certain clinical situations where no standard chronic treatment currently exists (e.g., CF, COPD, and CRS). We hypothesize that by encapsulating the stable NO-donor, S- nitroso-N-acetylpenicillamine (SNAP), into common polymeric tubing for iNO therapy, light-activated release of NO can be achieved to yield controlled therapeutic NO levels in the carrier air gas. To test this hypothesis, in Aim 1 we will characterize the variables of light active NO release from SNAP-loaded tubing into an airstream. We will load SNAP into polymeric tubing and ambient air will be delivered through the tubing while initiating photolytic NO release with a flood lamp. NO will be monitored to assess how formulation variables in the SNAP-loaded tubing influence the levels and lifetime of photolytic NO release. In Aim 2, we will combine LED light and a new NO sensor with the optimal SNAP-loaded tubing formulations from Aim 1 to monitor and achieve therapeutic NO levels. We will test how varying humidified air flow rates with optimal tubing type, geometry and SNAP loading can provide continuous, stable levels of NO within the target range of 200-2000 ppbv within an air stream for at least 10 h, using sensor signals to control LED intensity. In Aim 3, we will examine controlled iNO delivery using the system devised in Aim 2 for its ability to kill bacteria in vitro. We will grow biofilms of P. aureginosa and S. aureus and expose them for various times to specific iNO levels in a range of 200-2000 ppbv with humidified air. Biofilm biomass and viable bacteria will be determined to assess iNO effect derived from the SNAP-loaded tubing. Human tracheal epithelial cells grown on a semipermeable membrane at the air/liquid interface will also be treated with the iNO approach to prove that the produced NO levels have no adverse effects on these cells. The effect of various NO levels produced from the SNAP-loaded tubing on biofilms grown on the surface of the human epithelial cells will also be examined.

一氧化氮（NO）是一种潜力和内源性抗菌/抗病毒剂，通常存在于中等水平 （200-1000 ppbv）在健康患者的上呼吸道/鼻窦内，有助于防止慢性上呼吸道 感染。患有慢性鼻孔炎（CRS）和其他难以治疗的疾病患者 呼吸道感染 - chronic阻塞性肺疾病（COPD），囊性纤维化（CF）等 遗传的无治疗（INO）可能会受益于家庭治疗。而Ino的水平要高得多（10- 50 ppmv）通常在医院用于新生儿肺动脉高压和成人急性呼吸道 遇险综合征，当前INO系统的极高成本（每天$ 3,000）排除了它们的使用 与CRS，COPD和CF相关的呼吸道感染的家庭治疗。对于这种疾病， 施用NO的剂量通常在健康个体的上部呼吸道中发现的水平 可能是预防或治疗下呼吸道感染的安全有效方法。在此处， 我们建议研究一种新的低成本递送策略，以产生纯氧化氧化物（NO）用于INO治疗，这 可以在医院或在家中用于某些没有标准慢性治疗的临床情况 目前存在（例如CF，COPD和CRS）。我们通过封装稳定的无偏见，S-来假设这一点 硝基-N-乙酰苯胺（SNAP）进入常见的聚合管，以进行INO治疗，光激活的释放 无法实现载气气体中的受控治疗水平。为了检验这一假设， AIM 1我们将表征光主动的变量无释放，从加载的油管中释放到气流中。 我们将在开始时将扣子加载到聚合物管中，环境空气将通过管道传递 光解释没有洪水灯。不会监视不监视以评估公式变量如何 加载的管子会影响光子溶液无释放的水平和寿命。在AIM 2中，我们将结合LED Light和一个新的无传感器，具有AIM 1的最佳快照管道配方，以监视和 达到治疗没有水平。我们将通过最佳管道类型测试如何变化的加湿的空气流量， 几何和快照负载可以在目标范围内提供连续的，稳定的NO水平 使用传感器信号控制LED强度，在空气流中的PPBV至少10小时。在AIM 3中，我们将 使用AIM 2中设计的系统检查受控的INO递送，以便其体外杀死细菌的能力。我们将 种植P. aureginosa和S.金黄色葡萄球菌的生物膜，并将它们不同时间暴露于A 带有加湿空气的200-2000 ppbv范围。将确定生物膜生物量和可行细菌以评估 iNO效应从加载的油管中得出。人类气管上皮细胞生长在可半透明的 空气/液体界面处的膜也将使用INO方法处理，以证明该方法没有生产 水平对这些细胞没有不利影响。从扣子加载产生的各种无级别的效果 还将检查在人类上皮细胞表面生长的生物膜上的管道。