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）：北方大象的印章发展了强大的生理机制，使他们能够适应许多极端环境条件，这些环境状况会引起人类或其他哺乳动物会引起许多心血管和呼吸系统并发症。例如，所有大象密封件都经历了长达3个月的绝对食物和水剥夺时期，而没有表现出任何脱水或电解质失衡的指标。在1个月大时，幼崽突然断奶了，开始了2至3个月的快速，全部不断地开发潜水系统所需的器官系统，这些器官系统将在较快的后锻炼后随后发生。在海象密封时，通常会潜入超过500 m的深度，浸没了40-60分钟，然后在下一次潜水之前仅2-3分钟返回地面进行气体交换。此外，大象密封件表现出慢性（80％的时间）睡眠呼吸暂停（11分钟），可在3分钟内诱导40 mmHg的动脉P02。独立地，这些行为中的任何一种都可能引起许多心血管和呼吸并发症。然而，大象密封具有进化的机制来应对这些行为的有害影响，这在哺乳动物中是无与伦比的。因为该倡议将支持研究以开始阐明哺乳动物在独特地适应人类危及生命的心血管和呼吸反应的哺乳动物中进化的机制，所以大象印章为满足这些要求提供了理想的模型。该建议将在大象中阐明氧化应激和炎症的细胞和全身机制，通常与长期食物以及水剥夺和睡眠呼吸暂停有关。我们的具体目的是：1）阐明血管紧张素II对氧化应激和炎症的细胞机制的贡献，通过量化氧化应激的循环和细胞标记和细胞标记，在长期禁食期间长期禁食的循环和炎症，2），以增加对氧化应激的循环和氧化压力的贡献，并使氧化应力的循环含量增加，并在氧化应力的贡献中氧化，并在氧化压力的贡献中对氧化的贡献和氧化的影响。长时间禁食期间的氧化应激和炎症，3），以阐明在天然适应的大象密封剂中长时间睡眠呼吸暂停诱导的缺氧期间诱导的细胞抗氧化剂和抗炎机制。由于已知肾素血管紧张素系统（RAS）和皮质醇在该物种的禁食中会发生变化，因此我们将重点关注Ras和糖皮质激素对在禁食和睡眠呼吸暂停期间介导氧化应激和炎症的贡献。这些目标的完成将提供有关大象密封剂进化的适应机制的新信息，以最大程度地减少或减轻氧化应激和炎症的后果，通常与人类中旷日持久的食物剥夺和睡眠呼吸暂停有关，以识别新的治疗靶标。公共卫生相关性：除了慢性睡眠呼吸暂停引起的缺氧外，大象海豹还经历了长时间的食物和水剥夺时期，这两者都可能迅速引起人类的心血管和呼吸并发症。但是，这些密封必须发展出独特的鲁棒生理和细胞机制，以应对通常与这些行为相关的潜在有害后果。密封中阐明这些机制可能会揭示新的治疗靶标，以帮助减轻人类的这些后果。拟议的研究提供了开发北象密封的初步步骤，作为一种可行的生物医学模型，以研究与氧化应激和炎症事件相反，通常是由于长期食物剥夺以及与睡眠和潜水相关的缺氧所引起的。