Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, USA.
Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
J Physiol. 2020 Jan;598(2):317-329. doi: 10.1113/JP278991. Epub 2019 Dec 31.
Our tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma, including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fibre loss. Delayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved pain Losartan, an angiotensin-receptor blocker with anti-fibrotic abilities, recapitulates the effect of exercise on post-injury recovery and may provide an enhanced recovery option for those who are unable to exercise after injury ABSTRACT: Chronic pain and disability after limb injury are major public health problems. Early mobilization after injury improves functional outcomes for patients, although when and how to implement rehabilitation strategies remains a clinical challenge. Additionally, whether the beneficial effects of exercise can be reproduced using pharmacological tools remains unknown and may benefit patients who are unable to exercise as a result of immobilization. We developed a murine model of orthopaedic trauma combining tibia fracture and pin fixation with muscle damage. Behavioural measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microcomputed tomagraphic scanning, and muscle fibre size distribution and fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fibre size lasting up to 5 weeks from injury. We also observed that allowing 'late' (weeks 1-2) rather than 'early' (weeks 0-1) exercise after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was associated with reduced muscle fibrosis, earlier increase in muscle fibre diameter and a short-term benefit in reducing callus volume. Providing the anti-fibrotic angiotensin receptor blocker losartan to mice in drinking water reduced both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes and that losartan is a viable candidate for translational studies.
我们建立的小鼠骨科损伤模型可以重现复杂创伤的主要表现，包括痛觉过敏、骨折、肌肉纤维化和肌肉纤维丢失。复杂骨科创伤后延迟运动可导致肌肉纤维化减少和疼痛改善。具有抗纤维化能力的血管紧张素受体阻滞剂氯沙坦可重现运动对损伤后恢复的影响，并且可能为受伤后无法运动的患者提供增强的恢复选择。
四肢损伤后的慢性疼痛和残疾是主要的公共卫生问题。受伤后早期活动可改善患者的功能预后，尽管何时以及如何实施康复策略仍然是一个临床挑战。此外，运动的有益效果是否可以通过药理工具来复制仍然未知，并且可能使因固定而无法运动的患者受益。我们建立了一种结合胫骨骨折和针固定以及肌肉损伤的骨科创伤小鼠模型。行为学测量包括机械性痛觉过敏阈值和在运动轮上跑动的距离。使用微计算机断层扫描定量评估骨愈合，并用免疫组织化学检测肌肉纤维大小分布和纤维化。我们发现该模型提供了可靠的机械性感觉异常、纤维化以及受伤后长达 5 周的肌肉纤维平均大小向小转变。我们还观察到，受伤后允许“迟发性”（1-2 周）而不是“早期”（0-1 周）运动，会导致整体跑步活动增加，并更大程度地逆转感觉异常。平行地，迟发性跑步范式与肌肉纤维化减少、肌肉纤维直径更早增加以及短期减少骨痂体积有关。在饮水中给予抗纤维化血管紧张素受体阻滞剂氯沙坦可减轻感觉异常和肌肉纤维化。将氯沙坦与迟发性运动相结合没有额外的益处。我们得出结论，在开始运动之前，必须允许骨科创伤后早期愈合，以获得最佳的疼痛、功能和生理结果，氯沙坦是转化研究的可行候选药物。
