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）是一种有效的内源性抗微生物/抗病毒剂，通常以中等水平存在 （200-1000 ppbv）在健康患者的上气道/鼻窦内，有助于预防慢性上气道 感染.患有慢性鼻窦炎（CRS）和其他难以治疗的低血糖症的患者 呼吸道感染-慢性阻塞性肺病（COPD）、囊性纤维化（CF）等-可能 可能受益于吸入NO疗法（iNO）的家庭治疗。虽然iNO在更高的水平（10- 50 ppmv）在医院常规用于新生儿肺动脉高压和成人急性呼吸道疾病。 目前的iNO系统成本极高（每天3,000美元），因此无法用于 CRS、COPD和CF相关呼吸道感染的家庭治疗。对于这种疾病， 施用模拟健康个体上呼吸道中正常水平的NO剂量 可能是一种安全有效的预防或治疗上、下呼吸道感染的方法。在此， 我们建议研究一种新的低成本输送策略，以产生用于iNO治疗的纯一氧化氮（NO）， 可以在医院或家中用于某些临床情况， 当前存在（例如，CF、COPD和CRS）。我们假设，通过封装稳定的NO供体，S- 亚硝基-N-乙酰青霉胺（SNAP），进入用于iNO治疗的普通聚合物管，光激活释放 可以获得NO以在载气中产生受控的治疗NO水平。为了验证这一假设，在 目的1，我们将表征轻活性NO从SNAP加载管释放到气流中的变量。 我们将SNAP装入聚合物管中，启动时，环境空气将通过管输送 用泛光灯光解NO释放。将监测NO，以评估制剂变量在 SNAP加载管影响光解NO释放的水平和寿命。在目标2中，我们将联合收割机LED 光和一个新的NO传感器与最佳SNAP加载管配方从目标1监测和 达到治疗NO水平。我们将测试如何改变加湿空气流速与最佳管道类型， 几何形状和SNAP负载可以提供在200-2000的目标范围内的连续、稳定的NO水平 ppbv的空气流中至少10小时，使用传感器信号来控制LED强度。在目标3中，我们 使用目标2中设计的系统检查受控iNO递送的体外杀菌能力。我们将 生长生物膜的P. aureginosa和S.金黄色葡萄球菌，并将其暴露于特定的iNO水平的不同时间， 范围为200-2000 ppbv，加湿空气。将测定生物膜生物量和活菌，以评估 来自SNAP加载管的iNO效应。人气管上皮细胞在半透性培养板上生长 空气/液体界面处的膜也将用iNO方法处理，以证明所产生的NO 对这些细胞没有不良影响。从SNAP负载的细胞中产生的各种NO水平的影响 还将检查在人上皮细胞表面上生长的生物膜上的管。