Connective tissue and nervous system mechanisms of CAM therapies for low back pai

描述(申请人提供)：拉伸软组织(结缔组织和肌肉)是手法疗法(如按摩)和运动疗法(如瑜伽)的重要组成部分，在慢性和复发性下腰痛(LBP)的临床试验中已被证明是有效的。尽管来自临床试验的证据开始表明这些CAM疗法对慢性下腰痛(LBP)有效，但这些疗法有益的机制仍不清楚。我们假设1)结缔组织(CT)纤维化，伴随着神经系统的敏化，可以在实验上在猪的微损伤和运动限制的模型中产生，2)在这个猪模型中，结缔组织和神经系统的病理都是可逆的，并且可以通过组织拉伸来改善。该项目将为未来对人体组织拉伸影响的机械学研究奠定基础。我们将比较4组小型猪(48头猪，每组12头)，随机分为：1)腰部和骨盆限制活动8周；2)PCT微损伤后观察8周；3)PCT微损伤后限制活动8周；4)正常对照组。所有的猪都将接受每周超声波和使用无线定位传感器的步态分析(目标1)。然后，我们将比较两组猪(24头猪，每组12头)，所有猪都接受PCT微损伤加运动限制，持续时间由Aim1的结果确定，随后4周没有运动限制，在此期间，猪将被随机分为1)被动拉伸躯干或2)假拉伸(目标2)。对于这两个目标，主要的结果指标是PCT厚度(体内)、PCT剪切面运动(体内)、致密的PCT胶原束间距(体外)、乳晕PCT 1型前胶原含量和乳晕PCT硬度(体外)。次要观察指标包括步态节段间运动(体内)、乳晕PCT细胞介导的组织松弛(体外)、乳晕PCT神经源性炎症标志物(NGF、IL1-2和TNF-1)以及脊髓P物质和CGRP纤维密度。我们认为PCT纤维化和神经系统敏化是导致LBP慢性化的病理生理机制的关键组成部分，这种机制可以通过组织拉伸来逆转。未来的项目将在临床试验中使用基于超声的结缔组织结构和生物力学的非侵入性测量来测试这些病理异常的可逆性及其与临床改善的关系。我们的长期目标是将这种改进的机制理解作为制定合理的LBP综合治疗指南的基础，以获得最大的治疗效益。

DESCRIPTION (provided by applicant): Stretching of soft tissue (connective tissue and muscle) is an important component of manual (e.g. massage) and movement-based (e.g. yoga) CAM therapies that have been found to be efficacious in clinical trials of chronic and recurrent low back pain (LBP). Although evidence from clinical trials is beginning to show that these CAM treatments are effective in chronic low back pain (LBP), the mechanisms by which these treatments are beneficial remain unknown. We hypothesize that 1) connective tissue (CT) fibrosis, accompanied by nervous system sensitization, can be produced experimentally in a porcine model combining microinjury and movement restriction and 2) in this porcine model, both connective tissue and nervous system pathologies are reversible and can be ameliorated by tissue stretch. This project will set the stage for a future mechanistic study of the effect of tissue stretch in humans. We will compare four groups of mini-pigs (48 pigs, 12 pigs per group) randomized to: 1) movement restriction of the low back and pelvis for 8 weeks, 2) PCT microinjury followed by observation for 8 weeks, 3) PCT microinjury followed by movement restriction for 8 weeks and 4) normal controls. All pigs will undergo weekly ultrasound and gait analysis using wireless orientation sensors (Aim 1). We will then compare two groups of pigs (24 pigs, 12 pigs per group) all with PCT microinjury plus movement restriction for a duration determined by the results of Aim1, followed by 4 weeks without movement restriction during which pigs will be randomized to 1) passive stretching of the trunk or 2) sham stretching (Aim 2). For both Aims, primary outcome measures will be PCT thickness (in vivo), PCT shear plane motion (in vivo), dense PCT collagen bundle spacing (ex vivo), areolar PCT Type-1 procollagen content and areolar PCT stiffness (ex vivo). Secondary outcome measures will be intersegmental motion during gait (in vivo), areolar PCT cell-mediated tissue relaxation (ex vivo), markers of areolar PCT neurogenic inflammation (NGF, IL1-2 and TNF-1) and spinal cord Substance P and CGRP fiber density. We propose that PCT fibrosis and nervous system sensitization are key component of the pathophysiological mechanism leading to LBP chronicity that can be reversed by tissue stretch. Future projects will test the reversibility of these pathological abnormalities and their relationship to clinical improvement in clinical trials using ultrasound-based non-invasive measures of connective tissue structure and biomechanics. Our long term goal is to use this improved mechanistic understanding as a basis for the development of rational integrative treatment guidelines for LBP for maximum therapeutic benefit.