Resuscitation of smoke inhalation and burn injury with a thioredoxin mimetic

用硫氧还蛋白模拟物复苏烟雾吸入和烧伤

• 批准号: 8338756
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 29.15万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338756
• 关键词: 3-nitrotyrosine; ATP Synthesis Pathway; Acetylcysteine; Acute; Acute Lung Injury; Address; Aftercare; Amides; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Ascorbic Acid; Attenuated; Biological; Biological Models; Blood Vessels; Blood-Air Barrier; Breathing; Burn injury; Cardiac; Cells; Cleaved cell; Clinical; Clinical Research; Continuous Intravenous Infusion; Cultured Cells; Cysteine; Cytoplasmic Protein; DNA Repair Enzymes; DNA Single Strand Break; Development; Diffusion; Dose; Double-Blind Method; Drainage procedure; Drug Delivery Systems; Equilibrium; Exhibits; Free Radicals; Functional disorder; Gases; Generations; Genomics; Glucose; Glutathione; Glutathione Disulfide; Gold; Head; Heparin; Histologic; Hydrogen Peroxide; Hypersensitivity; Hypoxia; In Vitro; Infiltration; Inflammation; Inflammatory; Inhalation Burns; Injury; Inorganic Sulfates; Lipid Peroxidation; Lung; Lung Inflammation; Lymphatic; Measurement; Mediating; Medical; Modeling; Mus; Necrosis; Nitric Oxide; Nitrogen; Nuclear; Nuclear Translocation; Organ failure; Orphan Drugs; Oryctolagus cuniculus; Ovalbumin; Oxidants; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathway interactions; Patients; Peripheral; Peripheral Resistance; Peroxonitrite; Pharmaceutical Preparations; Placebo Control; Pneumonia; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Production; Proline; Prospective Studies; Proteins; Pulmonary Vascular Resistance; Randomized; Reaction; Relative (related person); Resistance; Respiratory Failure; Respiratory Insufficiency; Resuscitation; Sheep; Shunt Device; Signal Transduction; Smoke; Smoke Inhalation Injury; Stress; Study models; Sulfhydryl Compounds; Superoxides; Testing; Therapeutic; Thioredoxin; Tissues; Trauma; Unspecified or Sulfate Ion Sulfates; Up-Regulation; Water; airway obstruction; base; chlorine gas; clinical efficacy; clinically relevant; cytokine; drug market; exhaustion; functional loss; hemodynamics; improved; in vivo; indexing; injured; innovation; inorganic phosphate; lung injury; mimetics; mortality; neutrophil; novel; oxidant stress; oxidation; preclinical study; pressure; prospective; respiratory; small molecule; smoke inhalation; thioredoxin reductase; wet lung

DESCRIPTION (provided by applicant): Smoke inhalation and burn injury (SIBI) induces acute lung injury (ALI) via the generation of toxic free radical and oxidant species that, in turn, trigger DNA single strand breaks (SSB) throughout the pulmonary parenchyma. When this genomic injury is then recognized by the nuclear DNA repair enzyme poly(ADP-ribose) polymerase ("PARP"), NAD is cleaved to generate the product poly(ADP-ribose). Hyperactivation of PARP depletes NAD stores, resulting in the loss of oxidative phosphorylation and interference with ATP synthesis. In severe instances, the ultimate exhaustion of high energy phosphates (ATP) triggers cellular necrosis and the functional loss of the alveolocapillary membrane. To address this unmet clinical need and potential orphan drug market, we are developing a cell-permeable thioredoxin mimetic (R-901), a thiol-rich tripeptide that is closely analogous to the native thioredoxin (TRX) motif. R-901 exhibits in vitro potency 450- and 50-fold > than N-acetylcysteine (NAC) and ascorbic acid, respectively, and in vivo potency substantialy greater than NAC. Therapeutic administration of R-901 has been shown in a murine model of pulmonary inflammation (induced by ovalbumin sensitization and re-challenge) to reduce histologic injury, diminish neutrophil (PMN) infiltration, attenuate tissue oxidation, block pro-inflammatory cytokine expression and nuclear translocation of NF-?B, diminish the degradation of the anti-inflammatory cytoplasmic protein I?B¿, and restore the balance of reduced and oxidized forms of glutathione. In a murine LD100 model of severe redox stress induced by acute chlorine gas inhalation, post-insult administration of R-901 reduced pulmonary PMN infiltration by 50%. The Specific Aim of this proposal is to compare the potency of R-901 and NAC in an ovine model of combined SIBI-ALI. We will carry out a prospective, placebo-controlled, randomized, double-blinded, study in which respiratory insufficiency is induced in mechanically-ventilated Merino sheep by acute SIBI. Resuscitation with R-901, NAC, or vehicle control will be initiated 1 h after thermal insult and continued for 48 h, a timepoint characterized by massive respiratory failure. We expect that R-901 will demonstrate statistically significant superiority relative to NAC as noted for the following indices: 1) Reduced lung inflammation and injury, as manifested in lung wet/dry ratio, lymphatic drainage, lipid peroxidation, airway obstruction, histologic scoring, PMN infiltration, ONOO- (3-nitrotyrosine, "3-NT") formation, and poly(ADP-ribose) ("PAR") formation; 2) Improved hemodynamics and airway pressures, as revealed by reductions in pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (MPAP), and peak inspiratory pressure (PIP), without impacting systemic vascular resistance (SVR), mean peripheral arterial pressure (MAP), and cardiac index (CI); and 3) Reduced pulmonary shunt, as indicated by diminished arterioalveolar (Aa) gradient and an increased ratio of arterial O2 tension to inspired O2 concentration (PaO2/FiO2). These benefits, taken together, will justify continued development of R-901 for treatment of acute SIBI. PUBLIC HEALTH RELEVANCE: Smoke inhalation with associated burn injury is a leading cause of respiratory failure. At present, there is no approved therapy for this condition and mortality remains high. We are developing a novel drug that targets the basic mechanisms of lung injury in this condition and will test this agent in a clinically-relevant large animal model f trauma.

描述（由应用提供）：吸入和烧伤损伤（SIBI）通过产生有毒的自由基和氧化剂而诱导急性肺损伤（ALI） 在整个肺实质中触发DNA单链断裂（SSB）。当这种基因组损伤被核DNA修复酶聚（ADP-核糖）聚合酶（“ PARP”）识别时，NAD被切割以生成乘积聚（ADP-核糖）。 PARP的过度激活消耗NAD存储，导致氧化磷酸化和与ATP合成的干扰丧失。在严重的情况下，高能磷酸盐（ATP）的最终耗尽会触发细胞坏死和Alloolocillocillary膜的功能损失。为了满足这种未满足的临床需求和潜在的孤儿药市场，我们正在开发一种可渗透的硫氧还蛋白模拟物（R-901），这是一种与天然硫氧还蛋白（TRX）基序密切类似的富含硫醇的三肽。 R-901 exhibits in vitro potency 450- and 50-fold > than N-acetylcysteine ​​(NAC) and ascorbic acid,合に行はいます。 合に行はいます。 English: Therapeutic administration of R-901 has been shown in a murine model of pulmonary infection (induced by ovalbumin sensory and re-challenge) to reduce histologic injury, diminish neutrophil (PMN) infiltration, attenuate组织氧化，阻塞促炎性细胞因子表达和NF-？B的核易位，减少了抗炎细胞质蛋白I？b的降解，并恢复了谷胱甘肽的还原和氧化形式的平衡。在由急性氯气吸入引起的严重氧化还原应激的鼠LD100模型中，R-901的雾化后给药降低了50％的肺PMN PMN。该提案的具体目的是比较合并的Sibi-Ali卵巢模型中R-901和NAC的效力。我们将通过急性SIBI在机械通风的Merino绵羊中诱导一项前瞻性，安慰剂对照，随机，双盲的研究。用R-901，NAC或媒介物控制的复苏将在热侮辱后1小时开始，并持续48小时，这是一个以大规模呼吸衰竭为特征的时间点。 We expect that R-901 will demonstrate statistically significant superiority relative to NAC as noted for the following indices: 1) Reduced lung infection and injury, as manifested in lung wet/dry ratio, lymphatic drainage, lipid peroxidation, airway objection, histologic scoring, PMN infiltration, ONOO- (3-nitrotyrosine, "3-NT") formation, and poly(ADP-ribose) （“ PAR”）编队； 2）改善了血液动力学和气道压力，如肺血管耐药性（PVR）的降低，平均肺动脉压（MPAP）和峰值灵感压力（PIP），而没有影响全身血管耐药性（SVR），平均外周动脉压力（MAP）和心脏（MAP）和心脏指数（CI）； 3）减少了肺分流，如动脉肺泡（AA）梯度降低所示，动脉O2张力与受启发的O2浓度的比率增加（PAO2/FIO2）。这些好处共同证明，R-901用于治疗急性SIBI的持续发展是合理的。 公共卫生相关性：吸入与烧伤相关的烟雾是呼吸衰竭的主要原因。目前，对于这种情况尚无批准的治疗，死亡率仍然很高。我们正在开发一种新的药物，该药物靶向这种情况下的肺损伤基本机制，并将在临床上与大型动物模型F创伤中测试该药物。