Sepsis and the benefits of permissive hypoxia

脓毒症和允许性缺氧的好处

• 批准号: 10450186
• 负责人: Shahzad Shaefi
• 金额: $ 19.39万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450186
• 关键词: Acute; Adenosine; Adenosine Triphosphate; Admixture; Affect; Animal Model; Antiinflammatory Effect; Attention; Bacteremia; Bacterial Model; Biliverdine; Binding; Bioenergetics; Biological; Biological Process; Biology; Carbon Monoxide; Caring; Cell Death; Cell Hypoxia; Cell physiology; Cells; Cessation of life; Clinical; Critical Care; Critical Illness; Data; Development Plans; Disease; Ensure; Environment; Equilibrium; Exposure to; Free Radicals; Functional disorder; Funding; Gases; General Anesthesia; Generations; Goals; Health; Heme; Hemeproteins; Hospitals; Hyperoxia; Hypoxemia; Hypoxia; Hypoxia Pathway; Immune response; Impairment; Inflammation; Injury; Innate Immune Response; Intensive Care Units; Intervention; Intuition; Investigation; Iron; Lead; Link; Mediating; Mentorship; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Modernization; Morbidity - disease rate; Mus; Operating Rooms; Oxidative Stress; Oxygen; Oxygen Therapy Care; Palate; Patients; Perioperative Care; Persons; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Production; Program Development; Protein Glycosylation; Reactive Oxygen Species; Recovery; Research; Resolution; Role; Scientist; Sepsis; Site; Structure; Supplementation; Tissues; Titrations; Transcend; United States; Up-Regulation; Work; biological adaptation to stress; career development; cecal ligation puncture; experience; gene product; glycosylation; health care delivery; heme oxygenase-1; improved outcome; innovation; insight; mitochondrial dysfunction; mortality; mouse model; neutrophil; normoxia; novel; polymicrobial sepsis; pre-clinical; protective effect; response; skills; stressor; supplemental oxygen

PROJECT SUMMARY / ABSTRACT This project proposes a five-year research career development program focused on the study of permissive hypoxia in sepsis to expand the depth and breadth of understanding of the underlying mechanisms of mitochondrial dysfunction in this milieu. Currently, oxygen administration is the most widely administered drug in in-hospital care, and is liberally titrated to avoid potentially injurious periods of hypoxemia. Mounting evidence in several allied species suggest that not only is hyperoxia detrimental, but that local tissue hypoxia may in fact be beneficial to an evolved, requisite, and protective biological process. In critical illness such as sepsis, mitochondrial dysfunction is common, due in large part to oxidative stress, that results in impaired ATP generation, mitophagy, and in some cases, cell death. Strategies to mitigate or ameliorate this dysfunction and promote decreases in morbidity and mortality are therefore sought. Delivery of exogenously delivered carbon monoxide (CO) has stood out as a promising strategy because of its ability to simulate a protective hypoxic pathway. CO is generated endogenously by heme oxygenase-1 (HO-1) as part of the stress response. These molecules are potently salutary in models of sepsis and tissue hypoxia. Mechanistically, mitochondria are principal targets for these bioactive gases, with both oxygen and CO competing for binding to the large number of hemoproteins within the matrices. Using established models of bacterial sepsis in mice involving cecal ligation and puncture, this project will evaluate the role of HO-1/CO in mitigating mitochondrial dysfunction through modulation of inflammation. We will study the neutrophil where preliminary data suggest that these cells are influenced by CO. These models will be used to characterize the host response to sepsis and how oxygen titration affects mitochondrial function and survival. We will assess changes in mitochondrial function and protein glycosylation signatures linked to metabolsism known to be altered during hypoxia, investigate how mitochondria in the neutrophil are influenced by oxygen, and evaluate HO-1 and CO in promoting effective and appropriate bacterial clearance and resolution of inflammation. Guided by strong mentorship with significant expertise, this work has the opportunity to transcend observations around oxygen titration in the perioperative and critical care settings. Further, this project includes a well- structured and rigorous career development plan to build upon the candidates strong clinical and preclinical experience. Combined with an extraordinary environment and institutional support, the successful completion of the proposed project will provide the candidate with the skills and experience necessary to successfully compete for funding as an independent clinician scientist, with translational expertise in an innovative research niche.

项目摘要/摘要

项目成果

Anesthetic management of unruptured intracranial aneurysms: a qualitative systematic review.

• DOI: 10.1007/s10143-020-01441-w
• 发表时间: 2021-10
• 期刊: NEUROSURGICAL REVIEW
• 影响因子: 2.8
• 作者: Esmaeeli, Shooka;Valencia, Juan;Buhl, Lauren K.;Bastos, Andres Brenes;Goudarzi, Sogand;Eikermann, Matthias;Fehnel, Corey;Pollard, Richard;Thomas, Ajith;Ogilvy, Christopher S.;Shaefi, Shahzad;Nozari, Ala
• 通讯作者: Nozari, Ala

Effect of midodrine versus placebo on time to vasopressor discontinuation in patients with persistent hypotension in the intensive care unit (MIDAS): an international randomised clinical trial.

• DOI: 10.1007/s00134-020-06216-x
• 发表时间: 2020-10
• 期刊: Intensive care medicine
• 影响因子: 38.9
• 作者: Santer P;Anstey MH;Patrocínio MD;Wibrow B;Teja B;Shay D;Shaefi S;Parsons CS;Houle TT;Eikermann M;MIDAS Study Group
• 通讯作者: MIDAS Study Group

Anesthetics to Prevent Lung Injury in Cardiac Surgery: A Randomized Controlled Trial.

• DOI: 10.1053/j.jvca.2022.04.018
• 发表时间: 2022-10
• 期刊: Journal of cardiothoracic and vascular anesthesia
• 影响因子: 2.8

Proteomics for the Discovery of Clinical Delirium Biomarkers: A Systematic Review of Major Studies.

• DOI: 10.1213/ane.0000000000006246
• 发表时间: 2023-03-01
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7

Bleeding and thrombotic events in adults supported with venovenous extracorporeal membrane oxygenation: an ELSO registry analysis.

• DOI: 10.1007/s00134-021-06593-x
• 发表时间: 2022-03
• 期刊: INTENSIVE CARE MEDICINE
• 影响因子: 38.9
• 作者: Nunez, Jose, I;Gosling, Andre F.;O'Gara, Brian;Kennedy, Kevin F.;Rycus, Peter;Abrams, Darryl;Brodie, Daniel;Shaefi, Shahzad;Garan, A. Reshad;Grandin, E. Wilson
• 通讯作者: Grandin, E. Wilson