Mechanisms of Oxidative Stress and Inflammation during Prolonged Fasting and Slee

长时间禁食和睡眠期间氧化应激和炎症的机制

• 批准号: 8015226
• 负责人: Rudy M Ortiz
• 金额: $ 41.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, MERCED
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015226
• 关键词: 3-nitrotyrosine; 4 hydroxynonenal; Address; Age; Age-Months; Aldosterone; Angiotensin II; Angiotensin Receptor; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Behavior; Biological Markers; Breeding; C-reactive protein; California; Cardiovascular Diseases; Cardiovascular system; Chronic; Constitution; Corticotropin; Dehydration; Development; Dexamethasone; Discipline of Nursing; Diving; Drug Interactions; Effectiveness; Electrolytes; Enzymes; Event; Exhibits; Experimental Water Deprivation; Fasting; Female; Film; Food; Food deprivation (experimental); Gases; Gender; Glucocorticoid Receptor; Glucocorticoids; Glutathione S-Transferase; Goals; Health; Human; Hydrocortisone; Hypoxia; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Interleukin-6; Life; Lipid Peroxidation; Lung diseases; Mammals; Measurement; Measures; Mediating; Mifepristone; Mirounga; Modeling; Mothers; Muscle; Nitrates; Nitrites; Oxidative Stress; Partner in relationship; Physiological; Proteins; Receptor Signaling; Renin; Renin-Angiotensin System; Research; Resistance; SOD2 gene; Sea; Seasons; Sleep; Sleep Apnea Syndromes; Surface; TNF gene; Therapeutic Intervention; Time; Tissues; Tumor Necrosis Factor-alpha; Universities; Water; Weaning; body system; catalase; design; experience; fighting; glutathione peroxidase; human SOD2 protein; indexing; inflammatory marker; isoprostaglandin F2alpha type-III; life history; male; member; new therapeutic target; nitrosative stress; novel; prevent; pup; respiratory; response; seal

DESCRIPTION (provided by applicant): Northern elephant seals have evolved robust physiological mechanisms that have allowed them to adapt to a number of extreme environmental conditions that in humans or other mammals would evoke a number of cardiovascular and respiratory complications. For example, all elephant seals experience protracted periods of absolute food and water deprivation for up to 3 months without exhibiting any indices of dehydration or electrolyte imbalances. At 1 month of age, pups are abruptly weaned and commence a 2- 3 month long fast, all-the-while continuing to develop organ systems required for diving that will ensue following their postweaning fast. While at sea elephant seals routinely dive to depths in excess of 500 m remaining submerged for 40-60 mins followed by return to the surface for gas exchange for only 2-3 mins before the next dive. In addition, elephant seals exhibit chronic (80% of time) bouts of sleep apnea (11 min) that induce arterial P02 of 40 mmHg within 3 min. Independently, any of these behaviors could potentially evoke a number of cardiovascular and respiratory complications; however elephant seals have evolved mechanisms to counter the deleterious effects of these behaviors collectively, which is unparalleled amongst mammals. Because this initiative will support studies to begin to elucidate the mechanisms evolved in mammals uniquely adapted to extreme environmental conditions that evoke life-threatening cardiovascular and respiratory responses in humans, the elephant seal provides an ideal model to fulfill these requirements. This proposal will elucidate in elephant seals the cellular and systemic mechanisms of oxidative stress and inflammation commonly associated with prolonged food and water deprivation and sleep apnea. Our specific aims are: 1) to elucidate the contribution of elevated angiotensin II to the cellular mechanisms of oxidative stress and inflammation by quantifying circulating and cellular markers of oxidative stress and inflammation during prolonged fasting in elephant seals, 2) to elucidate the contribution of increased cortisol to the cellular mechanisms of oxidative stress and inflammation by quantifying circulating and cellular markers of oxidative stress and inflammation during prolonged fasting in elephant seals, and 3) to elucidate the cellular antioxidant and anti-inflammatory mechanisms induced during prolonged sleep apnea-induced hypoxia in naturally adapted elephant seals. Because the renin- angiotensin system (RAS) and cortisol are known to change with fasting in this species, we will focus on the contribution of RAS and glucocorticoids to mediating oxidative stress and inflammation during fasting and sleep apnea. Completion of these aims will provide novel information on the adapted mechanisms evolved by elephant seals to minimize or alleviate the consequences of oxidative stress and inflammation commonly associated with protracted food deprivation and sleep apnea in humans in an effort to identify novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Elephant seals experience prolonged periods of food and water deprivation in addition to chronic sleep apnea-induced hypoxia, both of which can rapidly evoke cardiovascular and respiratory complications in humans. However, these seals must have evolved uniquely robust physiological and cellular mechanisms to counter the potentially detrimental consequences commonly associated with these behaviors. Elucidation of these mechanisms in seals may reveal novel therapeutic targets to help alleviate these consequences in humans. The proposed studies provide the initial steps towards developing the Northern elephant seal as a viable biomedical model to study the natural adaptations evolved to counter oxidative stress and inflammatory events commonly induced by prolonged food deprivation and, sleep- and diving-associated hypoxia.

描述（由申请人提供）：北象海豹已经进化出强大的生理机制，使它们能够适应许多极端的环境条件，而这些条件在人类或其他哺乳动物中会引起许多心血管和呼吸系统并发症。例如，所有象海豹都会经历长达 3 个月的长时间绝对食物和水缺乏，但没有表现出任何脱水或电解质不平衡的迹象。 1 个月大时，幼犬突然断奶，并开始为期 2-3 个月的禁食，同时继续发育断奶后禁食后潜水所需的器官系统。在海中，象海豹通常会潜入超过 500 m 的深度，并在水下停留 40-60 分钟，然后返回水面进行气体交换，在下次潜水前仅进行 2-3 分钟。此外，象海豹表现出慢性（80% 的时间）睡眠呼吸暂停（11 分钟），导致动脉 P02 在 3 分钟内达到 40 mmHg。单独而言，任何这些行为都可能引发多种心血管和呼吸系统并发症。然而，象海豹已经进化出机制来集体对抗这些行为的有害影响，这在哺乳动物中是无与伦比的。由于这一举措将支持研究开始阐明哺乳动物独特适应极端环境条件的进化机制，这些条件会引起人类危及生命的心血管和呼吸系统反应，因此象海豹提供了一个理想的模型来满足这些要求。该提案将阐明象海豹氧化应激和炎症的细胞和系统机制，这些机制通常与长期食物和水缺乏以及睡眠呼吸暂停有关。我们的具体目标是：1) 通过量化象海豹长期禁食期间氧化应激和炎症的循环和细胞标记物，阐明血管紧张素 II 升高对氧化应激和炎症细胞机制的贡献，2) 阐明血管紧张素 II 升高的贡献通过量化象海豹长期禁食期间氧化应激和炎症的循环和细胞标记物，皮质醇对氧化应激和炎症的细胞机制的影响，以及3）阐明诱导的细胞抗氧化和抗炎机制在自然适应的象海豹中，长时间睡眠呼吸暂停导致缺氧。由于已知该物种的肾素-血管紧张素系统 (RAS) 和皮质醇会随着禁食而变化，因此我们将重点关注 RAS 和糖皮质激素在介导禁食和睡眠呼吸暂停期间的氧化应激和炎症方面的贡献。这些目标的完成将为象海豹进化出的适应机制提供新的信息，以最大限度地减少或减轻通常与人类长期食物匮乏和睡眠呼吸暂停相关的氧化应激和炎症的后果，从而努力确定新的治疗靶点。公共健康相关性：除了慢性睡眠呼吸暂停引起的缺氧之外，象海豹还经历了长时间的食物和水缺乏，这两种情况都会迅速引发人类心血管和呼吸系统并发症。然而，这些海豹必须进化出独特的强大的生理和细胞机制，以应对通常与这些行为相关的潜在有害后果。阐明海豹的这些机制可能会揭示新的治疗靶点，以帮助减轻人类的这些后果。拟议的研究为将北象海豹开发为可行的生物医学模型提供了初步步骤，以研究为对抗氧化应激和炎症事件而进化的自然适应，这些氧化应激和炎症事件通常由长期食物匮乏以及睡眠和潜水相关的缺氧引起。