Development of a Porcine Model of Carbon Monoxide Poisoning to Evaluate Cardiac and Mitochondrial Dysfunction

开发一氧化碳中毒猪模型以评估心脏和线粒体功能障碍

• 批准号: 10228097
• 负责人: DAVID H JANG
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228097
• 关键词: Acute; Address; Affect; Air; Anatomy; Animal Model; Animal Testing Alternatives; Animals; Area; Award; Biochemical; Bioenergetics; Biological Markers; Biology; Biomedical Research; Canis familiaris; Carbon Monoxide; Carbon Monoxide Poisoning; Cardiac; Cardiovascular system; Case Study; Catheters; Cause of Death; Cessation of life; Cities; Clinical; Complication; Consequentialism; Critical Illness; Data; Department chair; Detection; Development; Diagnostic; Disease; Disease model; Domestic Pig; Dose; Drosophila genus; Electron Transport; Emergency department visit; Ensure; Environment; Equipment; Exhibits; Exposure to; Family suidae; Fire - disasters; Functional disorder; Funding; Gases; Genetic; Goals; Heart Abnormalities; Heart Injuries; Hospital Costs; Human; Human Biology; Hyperbaric Oxygen; Hyperbaric Oxygenation; Hyperbaric Therapy; Impairment; Injury; Investigation; Isoflurane; Knowledge; Maps; Measurement; Measures; Medical Societies; Medicine; Mentors; Metabolic Biotransformation; Metabolic Pathway; Methods; Mitochondria; Molecular; Morbidity - disease rate; Myocardial dysfunction; National Heart, Lung, and Blood Institute; Nervous System Trauma; Neurologic; Non-Rodent Model; Organism; Pathway interactions; Patients; Phenotype; Physiologic intraventricular pressure; Physiological; Physiology; Poisoning; Reactive Oxygen Species; Reporting; Research; Research Personnel; Research Support; Resources; Respiration; Retrospective Studies; Rodent; Source; Specificity; Suicide attempt; Supportive care; Survivors; Sus scrofa; System; Techniques; Testing; The Sun; Therapy Clinical Trials; Time; Toxic effect; Toxicology; Training; Translating; Tube; United States; Work; Xenobiotics; Zebrafish; base; cardiovascular effects; career; clinical application; clinically relevant; disability; dosage; endotracheal; experience; heart function; human disease; improved; in vivo; innovation; lost earning; mitochondrial dysfunction; mortality; mouse model; new therapeutic target; nonhuman primate; novel strategies; novel therapeutics; organ injury; porcine model; preclinical trial; pressure; protein expression; response; skills; standard care; success; translational model

Carbon monoxide (CO) is a colorless and odorless gas that is an important cause of poisoning annually with an estimated 50,000 emergency department visits occurring in the US and it is a leading cause of poisoning death globally. Various sources include faulty heat generators, suicidal attempts and fires. It is estimated that CO poisoning in the US results in over $1 billion annually related to hospital costs and lost earnings. CO poisoning has high mortality and morbidity with effects at the cardiovascular and neurologic system. The most serious complication of consequential CO exposure is delayed neurological sequela which occurs in up to 50% of survivors. However, the cardiac sequalae is less defined as well as the underlying cellular dysfunction that may occur. Our own work demonstrates that there are alterations in mitochondrial function (both bioenergetic and dynamic) in CO poisoning. The standard treatment for CO poisoning recommended by the Undersea & Hyperbaric Medical Society is hyperbaric oxygen (HBO) therapy. At this time, both diagnostics and treatments are aimed at early supportive care and select use of hyperbaric therapy. There is significant debate with currently available biomarkers and treatment for CO poisoning requiring a new approach to therapy that is mechanism-driven. Based on these existing gaps, there are ongoing investigations for improved treatment based primarily on small animal studies. However, many agencies that oversee toxicological testing require use of both rodent and non-rodent species which is lacking at this time. There is a paucity of large animal models to study both cellular dysfunction and potential therapy in CO poisoning. The primary limitations that this R03 proposal seeks to address are the following: (1) limited mechanistic understanding at a cellular level with regard to mitochondrial function (bioenergetics and dynamics); (2) the adverse cardiovascular effects of CO poisoning and the underlying cellular dysfunction that may occur; (3) the lack of adequate large animal models that more closely mimic human physiology. We propose to develop a large animal model of CO poisoning using the domestic pig (Sus scrofa domesticus). The pig may be considered a translational model of biomedical research because of anatomical, physiological and biochemical similarity to humans. This R03 proposal is strongly supported by preliminary data and feasibility that will ensure success. The PI (Jang) currently holds a NHLBI K08 award and will specifically leverage his K-supported research skills and techniques focused in the area of mitochondrial medicine with the full support of both his departmental chair (Ben Sun, MD) and K08 mentor (Todd Kilbaugh, MD) along with the outstanding environment that incorporates state-of-the-art equipment. The data and methods obtained with this R03 award will allow the PI to submit a competitive R01 as an ESI.

一氧化碳（CO）是一种无色无味的气体，是每年中毒的重要原因 据估计，美国有50，000次急诊就诊，这是导致 全球中毒死亡各种来源包括错误的热发生器，自杀企图和火灾。是 据估计，在美国，一氧化碳中毒每年导致超过10亿美元的医院费用和损失。 收益。一氧化碳中毒具有较高的病死率和致残率，并对心血管和神经系统产生影响 系统最严重的并发症是迟发性神经系统后遗症， 发生在50%的幸存者身上。然而，心脏后遗症的定义以及潜在的 可能发生的细胞功能障碍。我们自己的工作表明，在线粒体中存在改变， 功能（生物能和动态）在CO中毒。一氧化碳中毒的标准治疗 由海底和高压医学会推荐的是高压氧（HBO）疗法。在这个 与此同时，诊断和治疗的目的都是早期支持性护理和选择性使用高压氧治疗。 对于目前可用的生物标志物和需要新的生物标志物的CO中毒治疗存在重大争议。 一种机制驱动的治疗方法。根据这些现有差距，正在进行调查， 主要基于小动物研究的改进治疗。然而，许多监管机构 毒理学测试需要同时使用啮齿动物和非啮齿动物物种，这在目前是缺乏的。有一个 缺乏大型动物模型来研究CO中毒的细胞功能障碍和潜在治疗。 本R 03提案寻求解决的主要局限性如下：（1）有限的机械性 在细胞水平上理解线粒体功能（生物能量学和动力学）;（2） CO中毒的不良心血管效应和可能发生的潜在细胞功能障碍;（3） 缺乏足够的大型动物模型，更接近地模仿人类生理学。 我们建议用家猪（Sus scrofa）建立一个大的CO中毒动物模型 Aristoticus）。猪可以被认为是生物医学研究的转化模型， 与人类的生理和生化相似性。R 03提案得到初步支持 数据和可行性，这将确保成功。PI（Jang）目前持有NHLBI K 08奖，并将 特别是利用他的K支持的研究技能和技术集中在线粒体领域， 在他的系主任（Ben Sun，MD）和K 08导师（托德基尔博， MD）沿着而来的是采用最先进设备的出色环境。的数据和 通过R 03获得的方法将允许PI提交具有竞争力的R 01作为ESI。

项目成果

Preliminary Research: Application of Non-Invasive Measure of Cytochrome c Oxidase Redox States and Mitochondrial Function in a Porcine Model of Carbon Monoxide Poisoning.

初步研究：细胞色素c氧化酶氧化还原状态和线粒体功能的非侵入性测量在一氧化碳中毒猪模型中的应用。

• DOI: 10.1007/s13181-022-00892-5
• 发表时间: 2022
• 期刊: Journal of medical toxicology : official journal of the American College of Medical Toxicology
• 作者: Lewis,Alistair;Forti,RodrigoM;Alomaja,Oladunni;Mesaros,Clementina;Piel,Sarah;Greenwood,JohnC;Talebi,FatimaM;Mavroudis,ConstantineD;Kelly,Matthew;Kao,Shih-Han;Shofer,FrancesS;Ehinger,JohannesK;Kilbaugh,ToddJ;Baker,WesleyB
• 通讯作者: Baker,WesleyB

Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat.

琥珀酸盐前药作为大鼠氟乙酸中毒期间急性代谢危机的治疗。

• DOI: 10.1007/s11010-022-04589-9
• 发表时间: 2023-06
• 期刊: Molecular and cellular biochemistry
• 影响因子: 4.3

Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning.

• DOI: 10.1038/s41598-022-24472-3
• 发表时间: 2022-11-25
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Piel S;Janowska JI;Ward JL;McManus MJ;Jose JS;Starr J;Sheldon M;Clayman CL;Elmér E;Hansson MJ;Jang DH;Karlsson M;Ehinger JK;Kilbaugh TJ
• 通讯作者: Kilbaugh TJ

Imaging of White Matter Injury Correlates with Plasma and Tissue Biomarkers in Pediatric Porcine Model of Traumatic Brain Injury.

在小儿猪创伤性脑损伤模型中，白质损伤的成像与血浆和组织生物标志物相关。

• DOI: 10.1089/neu.2022.0178
• 发表时间: 2023
• 期刊: Journal of neurotrauma
• 影响因子: 4.2
• 作者: Shin,SamuelS;Chawla,Sanjeev;Jang,DavidH;Mazandi,VanessaM;Weeks,MKatie;Kilbaugh,ToddJ
• 通讯作者: Kilbaugh,ToddJ

Alterations in cerebral and cardiac mitochondrial function in a porcine model of acute carbon monoxide poisoning.

• DOI: 10.1080/15563650.2020.1870691
• 发表时间: 2021-09
• 期刊: Clinical toxicology (Philadelphia, Pa.)
• 作者: Jang DH;Piel S;Greenwood JC;Kelly M;Mazandi VM;Ranganathan A;Lin Y;Starr J;Hallowell T;Shofer FS;Baker WB;Lafontant A;Andersen K;Ehinger JK;Kilbaugh TJ
• 通讯作者: Kilbaugh TJ