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）： 该应用程序的长期目标是更好地了解危害疾病肌病对隔膜（DIA）肌肉功能的影响；专注于功能障碍的分子机制。重症监护病房获得的肌肉无力，称为“临界肌肌病”，通常发生在接受长时间的机械通气的患者中，结合了神经肌肉连接阻塞剂（NMBA）和皮质类固醇（甲基丙酮，MP）。这些患者难以通过机械通气而断奶。 DIA功能障碍的机制尚不清楚，但可能是多因素的。包括增强的蛋白水解作为关键因素。泛素 - 蛋白酶体是骨骼肌中重要的蛋白水解系统。但是，目前未知的是上游途径的作用 - 即在控制机械通气（CMV）与NMBA和MP结合使用的DIA肌肉内的IGF-1/PI3K/AKT/FOXO和MP。我们最近的初步研究 - 比较了CMV，高剂量MP或CMV-MP的2天 - 表明DIAL力和IGF-1 mRNA降低了，表明这些病理扰动激活了常见的信号传导途径。但是，未知的是，CMV-NMBA与高剂量MP的组合是否会产生类似的DIA功能障碍，或者是由相似机制产生的。此外，没有关于RHIGF-1的体内给药是否会减轻DIA功能障碍的信息。该应用描述了两个特定目的，以检验以下假设：i）CMV-NMBA加MP对DIA功能的影响是剂量依赖性的，低剂量MP由于通过AKT/MTOR和MTOR的蛋白质合成增加而保护DIA功能，因此可以保护DIA功能。通过AKT/FOXO途径减少蛋白水解。我们将确定3天的CMV-NMBA的相互作用，而没有高剂量MP或低剂量MP在DIA收缩，结构和分子特性上的相互作用。如果合并的CMV-NMBA加上低剂量MP可保留与对照组相当的DIA力量产生，我们的假设将得到支持。 ii）RHIGF-1减轻DIA力量损失。在CMV-NMBA加MP期间，我们将比较仅RHIGF-1的3天的影响；在DIA收缩，结构性和分子特性上合并的RHIGF-1 Plus PI3K抑制剂（WORTMANNIN）或RHIGF-1和MTOR抑制剂（雷帕霉素）的组合。如果RHIGF-1治疗可防止DIA势损失，而使用RHIGF-1加Plus PI3K抑制剂或MTOR抑制剂消除其有益作用，则我们的假设将得到支持。将研究无病原体的新西兰白兔子。在特定的目标I中，这些动物将被随机分为四组，即接受CMV-NMBA（Cisatracurium）3天； CMV-NMBA-MP3（3 mg/kg/d），CMV-NMBA-MP30（30 mg/kg/d）或0 cm H2O的连续正气道压力（CPAP [Control]）。在特定目标II中，由特定目的治疗的动物组进一步分为亚组，仅接受RHIGF-1，RHIGF-1 Plus wortmannin或雷帕霉素。功能，形态学，生化；将进行DIA的细胞/分子测量。 公共卫生相关性： 与退伍军人卫生相关的三分之一的患者接受了重症监护病房（ICU）需要机械通气。启动机械通气的主要指示是急性呼吸衰竭。当排除术后原因时，肺炎，慢性阻塞性肺疾病（COPD）和充血性心力衰竭构成了发起机械通气的三大原因。所有三个诊断在退伍军人人口中都普遍存在，COPD占很大一部分的患者。这些患者中有许多需要皮质类固醇和机械通气支持，以在其疾病加剧后的各个持续时间内。另外，当该疾病（例如肺炎）演变成急性呼吸遇险综合征（ARDS）时，可能会使用瘫痪的药物来促进机械通气。尽管短期，高剂量皮质类固醇在COPD加剧或短期瘫痪药物给药以改善患者 - 易位者的相互作用或减少炎症细胞因子的产生方面有效，但这些都是获得肌肉无力的危险因素。获得的肌肉无力与长时间的断奶时间和更长的机械通气持续时间有关，不仅是住院护理，而且还与门诊康复有关。拟议的研究将阐明症状肌病的早期发育的机制，以及低剂量皮质类固醇或现有药物的潜在治疗可能预防。该研究有可能刺激药物的发展以改善或防止获得的肌肉无力。