Intermittent Hypoxia-Induced Inflammation Modulates Respiratory Plasticity

间歇性缺氧引起的炎症调节呼吸可塑性

• 批准号: 8791340
• 负责人: Gordon S. Mitchell
• 金额: $ 57万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791340
• 关键词: Acute; Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Breathing; Cell Nucleus; Central Nervous System Diseases; Cervical; Cervical spinal cord structure; Chronic lung disease; Clinical; Data; Development; Disease; Elements; Flow Cytometry; Gene Expression; Generations; Goals; HTR2A gene; Health; Human; Hypoxia; Inflammation; Inflammatory; Knowledge; Label; Life; Lipopolysaccharides; Lung; Lung diseases; MAPK14 gene; Microglia; Modeling; Motor; Motor Neuron Disease; Motor Neurons; Neurodegenerative Disorders; Neurotrophic Tyrosine Kinase Receptor Type 2; Obstructive Sleep Apnea; Okadaic Acid; PTGS2 gene; Pathology; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Protein Analysis; Protein phosphatase; Proteins; Public Health; Rattus; Respiratory Diaphragm; Signal Transduction; Spinal; Spinal Injuries; Structure of phrenic nerve; Study models; System; Testing; Therapeutic; Tissue-Specific Gene Expression; Vascular Endothelial Growth Factor Receptor; Work; cell type; cytokine; experience; innovation; interdisciplinary approach; mitogen-activated protein kinase p38; neuromechanism; novel therapeutics; prevent; relating to nervous system; respiratory; response; serotonin 7 receptor

PROJECT SUMMARY/ABSTRACT Factors that undermine the neural system controlling breathing diminish the capacity to compensate for pathology, threatening life itself. Plasticity is an essential feature of neural systems, including the neural system controlling breathing. The fundamental hypothesis guiding this proposal is that systemic inflammation impairs respiratory motor plasticity, undermining the ability to compensate for multiple pathologies, including chronic lung disease, traumatic, ischemic and degenerative neural disorders, and obstructive sleep apnea. We propose to investigate mechanisms whereby inflammation impairs a well-studied model of respiratory motor plasticity, phrenic long-term facilitiation (pLTF) following acute intermittent hypoxia. We will contrast inflammation induced by lipopolysaccharide (LPS) with that induced by one day of severe intermittent hypoxia (sIH); sIH simulates aspects of obstructive sleep apnea, a widespread clinical disorder with major implications for human health. Exciting preliminary data suggest that both LPS and sIH block pLTF via spinal inflammation. Since LPS and sIH elicit differential gene expression in different spinal cell types, yet have similar effects on pLTF, we propose a unifying hypothesis whereby multiple inflammatory molecules converge on a common "downstream" signaling cascade that constrains respiratory motor plasticity. An innovative, multidisciplinary approach will be used to test our hypotheses; experimental approaches include: phrenic nerve recordings in anesthetized rats, diaphragm EMG recordings in unanesthetized rats, immunohistochemical analysis of proteins in labeled phrenic motor neurons, analysis of inflammatory gene expression in freshly-isolated spinal astrocytes and microglia, and flow cytometry to assess proteins in identified cell types. Five specific hypotheses will be tested to advance our understanding: 1) Systemic LPS and sIH elicit spinal inflammation, thereby impairing phrenic and diaphragm LTF; 2) LPS and sIH differentially impair distinct pathways to phrenic motor facilitation (pMF). We will determine LPS and sIH effects on ERK- dependent (eg. pLTF), Akt-dependent and ERK/Akt-dependent pMF; 3) LPS and sIH elicit distinct inflammatory profiles. sIH affects only spinal microglia, whereas LPS also affects astrocytes; 4) Despite different inflammatory profiles, LPS and sIH impair pLTF by a common "downstream" mechanism involving p38 MAP kinase activation in phrenic motor neurons; and 5) Spinal p38 activity increases protein phosphatase 2A activity in phrenic motor neurons, thereby inhibiting ERK and constraining pLTF. Understanding mechanisms whereby inflammation undermines respiratory plasticity is of fundamental importance since inflammation may diminish the capacity for natural, compensatory plasticity during pathological states. Our long-range goal is to harness and promote respiratory plasticity as a therapeutic strategy to treat devastating breathing disorders, such as during cervical spinal injury or motor neuron disease.

项目摘要/摘要 破坏控制呼吸的神经系统的因素会减少补偿的能力 病理学，威胁生命本身。可塑性是神经系统的重要特征，包括神经系统 控制呼吸。基本的假设指导了这一提议，是系统性炎症 损害呼吸运动可塑性，破坏补偿多种病理的能力， 包括慢性肺部疾病，创伤性，缺血性和退化性神经疾病以及阻塞性睡眠 呼吸暂停。我们建议调查机制，从而使炎症损害了一个充分研究的模型 急性间歇性缺氧后，呼吸运动可塑性，长期促进（PLTF）。我们将 脂多糖（LPS）引起的对比度炎症，并引起严重的间歇性炎症 缺氧（SIH）； SIH模拟阻塞性睡眠呼吸暂停的各个方面，这是一种广泛的临床障碍 对人类健康的影响。令人兴奋的初步数据表明，LPS和SIH Block PLTF通过脊柱 炎。由于LPS和SIH在不同的脊柱细胞类型中引起差异基因表达，但 对PLTF的类似影响，我们提出了一个统一的假设，其中多种炎症分子 收敛于约束呼吸运动可塑性的常见“下游”信号级联。 一种创新的多学科方法将用于检验我们的假设；实验方法 包括：麻醉大鼠中的神经记录，未经麻醉大鼠的隔膜EMG记录， 标记为伪运动神经元的蛋白质的免疫组织化学分析，炎症基因的分析 在新鲜分离的脊髓星形胶质细胞和小胶质细胞中的表达，以及流式细胞术，以评估蛋白质中的蛋白质 确定的细胞类型。将测试五个特定的假设以提高我们的理解：1）系统性LPS SIH引起脊柱炎症，从而损害phrenic和diaphragm ltf； 2）LPS和SIH差异 损害运动促进性（PMF）的不同途径。我们将确定LP和SIH对ERK-的影响 依赖（例如PLTF），依赖AKT和ERK/AKT依赖性PMF； 3）LPS和SIH引起明显的炎症 概况。 SIH仅影响脊柱小胶质细胞，而LP也影响星形胶质细胞。 4）尽管不同 通过涉及p38地图的常见“下游”机制，炎症曲线，LP和SIH损害了PLTF Phrenic运动神经元中的激酶激活； 5）脊柱p38活性增加了蛋白质磷酸酶2a 伪运动神经元的活性，从而抑制ERK和约束PLTF。了解机制 由于炎症可能 在病理状态下，自然，代偿可塑性的能力降低。我们的远程目标是 利用和促进呼吸可塑性，作为治疗毁灭性呼吸障碍的治疗策略， 例如在颈椎损伤或运动神经元疾病期间。