Mechanisms of diaphragm muscle dysfunction in critical-illness myopathy

危重症肌病膈肌功能障碍的机制

• 批准号: 8258637
• 负责人: Catherine S Sassoon
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258637
• 关键词: 1-Phosphatidylinositol 3-Kinase; 70-kDa Ribosomal Protein S6 Kinases; Acute; Acute respiratory failure; Adrenal Cortex Hormones; Adult Respiratory Distress Syndrome; Adverse effects; Affect; Animal Model; Animals; Binding; Biochemical; Boxing; Caring; Cell Nucleus; Cells; Chronic Obstructive Airway Disease; Congestive Heart Failure; Continuous Positive Airway Pressure; Critical Illness; Critical Illness Polyneuropathy; Development; Dexamethasone; Diagnosis; Disease; Dose; F Box Domain; Functional disorder; Generations; Genetic Transcription; Glycogen Synthase Kinases; Health; Hospitals; Human; Impairment; Inflammatory; Inpatients; Insulin-Like Growth Factor I; Intensive Care Units; Intervention; Laboratories; Length of Stay; Light; Malnutrition; Measurement; Measures; Mechanical ventilation; Mechanics; Mediating; Membrane; Messenger RNA; Methylprednisolone; Methylprednisolone Sodium Succinate; Molecular; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Myopathy; Neural Conduction; Neuromuscular Diseases; Neuromuscular Junction; New Zealand; Observational Study; Oryctolagus cuniculus; Outpatients; Paralysed; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Pneumonia; Population; Postoperative Period; Prevention; Process; Production; Property; Prospective Studies; Protein Biosynthesis; Protein Dephosphorylation; Protein-Serine-Threonine Kinases; Proteins; Proteolysis; Randomized; Rattus; Recombinant IGF-I; Recovery of Function; Rehabilitation therapy; Reporting; Research; Respiratory Diaphragm; Ribosomal Protein S6; Ring Finger Domain; Risk Factors; Role; Sensory; Sepsis; Signal Pathway; Sirolimus; Skeletal Muscle; Subgroup; Survivors; System; Testing; Time; Translations; Treatment Cost; Ubiquitin; Ventilator; Veterans; Weaning; clinically relevant; cytokine; density; drug development; experience; human FRAP1 protein; improved; in vivo; interest; kinase inhibitor; mTOR Inhibitor; mTOR protein; multicatalytic endopeptidase complex; muscular structure; neuromuscular; pathogen; prevent; protein degradation; public health relevance; ubiquitin-protein ligase; wortmannin

DESCRIPTION (provided by applicant): The long-term objectives of this application are to develop a better understanding of the effects of critical- illness myopathy on diaphragm (DIA) muscle function; focusing on the molecular mechanisms of the dysfunction. Acquired muscle weakness in the Intensive Care Unit, referred to "critical-illness myopathy," occurs commonly in patients receiving prolonged mechanical ventilation combined with both neuromuscular junction blocking agents (NMBA) and corticosteroid (methylprednisolone, MP). These patients have difficulty weaning from mechanical ventilation. The mechanisms of DIA dysfunction are unknown, but are likely multifactorial; including enhanced proteolysis as a key factor. The ubiquitin-proteasome is an important proteolytic system in skeletal muscle. However, currently unknown is the role of upstream pathways -- i.e., the IGF-1/PI3K/Akt/Foxo within the DIA muscle under controlled mechanical ventilation (CMV) combined with NMBA, and MP. Our recent preliminary studies -- comparing 2 days of CMV, high-dose MP, or combined CMV-MP -- showed that DIA force and IGF-1 mRNA were reduced to the same extent, suggesting that these pathological perturbations activate a common signaling pathway. However, unknown is whether the combination of CMV-NMBA with high- or low-dose MP produces similar levels of DIA dysfunction, or results from similar mechanisms. Additionally, no information is available about whether in vivo administration of rhIGF-1 will mitigate DIA dysfunction. This application describes two specific aims to test the hypothesis that I) the effects of CMV-NMBA plus MP on DIA function is dose-dependent, with low-dose MP being protective of DIA function due both to increased protein synthesis via Akt/mTOR and decreased proteolysis via Akt/Foxo pathway. We will determine the interactive effects of 3 days of CMV-NMBA without or with high- or low-dose MP on DIA contractile, structural and molecular properties. Our hypothesis will be supported if the combined CMV-NMBA plus low-dose MP preserves DIA force production comparable to that in controls. II) rhIGF-1 mitigates DIA force-loss. During CMV-NMBA plus MP, we will compare the effects of 3 days of rhIGF-1 alone; combined rhIGF-1 plus PI3K-inhibitor (wortmannin), or combined rhIGF-1 plus mTOR- inhibitor (rapamycin) on DIA contractile, structural, and molecular properties. Our hypothesis will be supported if rhIGF-1 treatment prevents DIA force-loss, while treatments with rhIGF-1 plus either PI3K inhibitor, or mTOR inhibitor abolishes its beneficial effects. Pathogen-free New Zealand White rabbits will be studied. In Specific Aim I, the animals will be randomly assigned into four groups receiving either 3 days of CMV-NMBA (cisatracurium); CMV-NMBA-MP3 (3 mg/kg/d), CMV-NMBA-MP30 (30 mg/kg/d) or 0 cm H2O of continuous positive airway pressure (CPAP [control]). In Specific Aim II, groups of animals treated per Specific Aim I will be further divided into subgroups to receive rhIGF-1 alone, rhIGF-1 plus either wortmannin, or rapamycin. Functional, morphological, biochemical; cellular/molecular measurements of the DIA will be performed. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health One-third of patients admitted to the Intensive Care Unit (ICU) require mechanical ventilation. The major indication for the initiation of mechanical ventilation is acute respiratory failure. When post-operative causes are excluded, pneumonia, chronic obstructive pulmonary disease (COPD), and congestive heart failure comprise the top three reasons for initiating mechanical ventilation. All three diagnoses are prevalent in the veteran populations, with COPD comprising a large proportion of patients. Many of these patients require corticosteroid and mechanical ventilatory support for various durations following exacerbation of their disease. In addition, when the disease (e.g., pneumonia) evolves into or manifests as acute respiratory distress syndrome (ARDS), a paralyzing drug may be administered to facilitate mechanical ventilation. Despite the efficacy of short-term, high- or low-dose corticosteroid in COPD exacerbation, or of short-term paralyzing drug administration to improve patient-ventilator interaction, or to reduce inflammatory cytokine production, these are risk factors for acquired muscle weakness. Acquired muscle weakness is associated with prolonged weaning time and longer duration of mechanical ventilation, longer ICU and hospital stay, and increased treatment costs, not only for inpatient care, but also for outpatient rehabilitation. The proposed study will shed light on the mechanisms of early development of critical-illness myopathy, and its possible prevention with low- dose corticosteroid or potential treatment with existing drugs. The study has the potential to stimulate developments of drugs to ameliorate or prevent acquired muscle weakness.

描述(由申请人提供)： 这项应用的长期目标是更好地了解危重病肌病对隔肌(DIA)肌肉功能的影响；重点研究这种功能障碍的分子机制。重症监护病房的获得性肌肉无力，称为“危重肌病”，通常发生在接受长期机械通气并同时使用神经肌肉接头阻滞剂(NMBA)和皮质类固醇(甲基强的松龙，MP)的患者。这些患者在撤机时遇到困难。DIA功能障碍的机制尚不清楚，但可能是多因素的；包括作为关键因素的蛋白分解增强。泛素-蛋白酶体是骨骼肌中重要的蛋白分解系统。然而，目前尚不清楚上游通路的作用--即在控制性机械通气(CMV)联合NMBA和MP的情况下，DIA肌肉中的IGF-1/PI3K/Akt/FOXO。我们最近的初步研究--比较CMV、大剂量MP或CMV-MP联合用药2天--显示DIA力和IGF-1mRNA的降低程度相同，这表明这些病理扰动激活了共同的信号通路。然而，尚不清楚CMV-NMBA与高剂量或低剂量MP联合使用是否会产生类似水平的DIA功能障碍，或者是由类似的机制导致的。此外，目前还没有关于体内应用重组人胰岛素样生长因子-1是否会缓解DIA功能障碍的信息。本申请描述了两个特定的目的来检验假设：1)CMV-NMBA和MP对DIA功能的影响是剂量依赖的，低剂量的MP通过Akt/mTOR增加蛋白质合成和通过Akt/FOXO途径减少蛋白质分解而保护DIA功能。我们将确定3天的CMV-NMBA单独或与高或低剂量的MP对DIA收缩、结构和分子特性的交互影响。如果联合使用CMV-NMBA和低剂量的MP维持DIA的力量产生与对照组相当，我们的假设将得到支持。2)重组人胰岛素样生长因子-1减轻DIA的力量损失。在CMV-NMBA+MP期间，我们将比较单独使用3天的重组人IGF-1、联合使用PI3K-抑制剂(Wortmannin)或联合使用rhIGF-1+mTOR-抑制剂(雷帕霉素)对DIA收缩、结构和分子特性的影响。如果rhIGF-1治疗可以阻止DIA的力量丧失，那么我们的假设将得到支持，而rhIGF-1加上PI3K抑制剂或mTOR抑制剂的治疗则取消了其有益的效果。将对无病原体的新西兰白兔进行研究。在特定目的I中，动物将被随机分成四组，分别接受3天的CMV-NMBA(顺式阿曲库铵)、CMV-NMBA-MP3(3 mg/kg/d)、CMV-NMBA-MP30(30 mg/kg/d)或0 cm H2O的持续气道正压(CPAP)[对照]。在特定目标II中，按特定目标I处理的动物分组将被进一步分为单独接受重组人IGF-1、重组人IGF-1加Wortmannin或雷帕霉素的亚组。将进行DIA的功能、形态、生化、细胞/分子测量。 公共卫生相关性： 与退伍军人健康的相关性重症监护病房(ICU)三分之一的患者需要机械通风。启动机械通气的主要指征是急性呼吸衰竭。如果排除术后原因，肺炎、慢性阻塞性肺疾病(COPD)和充血性心力衰竭是启动机械通气的三大原因。所有这三种诊断在退伍军人中都很常见，其中慢性阻塞性肺病占患者的很大比例。这些患者中的许多人在病情恶化后需要不同时间的皮质类固醇和机械通气支持。此外，当疾病(如肺炎)演变为或表现为急性呼吸窘迫综合征(ARDS)时，可给予麻痹药物以促进机械通气。尽管短期、大剂量或小剂量的皮质类固醇对COPD的恶化有效，或者短期的麻痹用药以改善患者与呼吸机的相互作用，或减少炎性细胞因子的产生，这些都是获得性肌肉无力的危险因素。获得性肌肉无力与更长的撤机时间和更长的机械通气时间、更长的ICU和住院时间以及更高的治疗成本相关，不仅是住院护理，而且是门诊康复。这项拟议的研究将阐明危重病肌病早期发展的机制，以及小剂量皮质类固醇或现有药物潜在治疗对其可能的预防作用。这项研究有可能刺激药物的开发，以改善或防止获得性肌肉无力。