Modulation of inflammation and tissue repair by mast cells in skeletal muscle

除了少数营养不良疾病外，肌腱单位的损伤并不是一种危及生命的疾病，而是在运动和工作场所非常常见的问题。在加拿大，这类伤害每年造成2200,000天的医院护理(加拿大信息研究所)。在美国，2001年在美国运动医学院会议上公布的统计数据显示，肌肉骨骼疾病导致2100万个上学日和1.47亿个工作日的损失。据估计，这一切每年要花费2500亿美元。因此，每年有300亿片非甾体抗炎药被消费。这显然是社会上最被忽视的创伤之一。虽然必须提出预防护理措施，但更好地了解肌肉组织损伤和修复背后的机制将导致对这些损伤的更好管理，以及更具成本效益的治疗和战略。组织修复是一系列精心策划的细胞事件，涉及炎症细胞，这些细胞必须首先离开血流，然后才能与受损组织相互作用并导致修复。在目前的提案中，我们打算确定哪些细胞可以产生有助于炎症持续或消退的促炎或抗炎信号，以及哪些细胞可以触发组织修复。我们还想要描述每一个这些细胞的含义的时间框架。在这项提案中，我们将更具体地关注一种类型的免疫细胞，即肥大细胞。我们的工作假设是，肥大细胞发挥关键作用，不仅在调控炎症反应，而且在调节其分辨率和组织修复阶段。因此，我们将1)评估肥大细胞激活在肌肉损伤中调节炎性细胞侵袭的重要性；2)确定肥大细胞是否通过产生抗炎介质来帮助消炎；3)研究肥大细胞在肌肉愈合再生阶段的潜在意义及其作用机制。大多数情况下使用的模型是注射有毒药物造成的大鼠后肢肌肉损伤。

Except for a few dystrophic diseases, injury to muscle-tendon unit is not a life threatening disease, but a very common problem in sports and in the work place. This class of injury accounts for 2,200,000 days of hospital care every year in Canada (Canadian Institute of Information). In USA, statistics released in 2001 at the American College of Sports Medicine meeting reveal that musculoskeletal disorders account for the loss of 21 millions school days and 147 millions work days. It was estimated that all this costs $250 billions a year. Consequently, 30 billions NSAID tablets are consumed every year. It is clearly one of the most neglected class of trauma in society. While preventive care measures have to be put forward, a better understanding of the mechanisms behind muscle tissue injury and repair will lead to a better management of these injuries and to more cost-effective treatments and strategies. Tissue healing is a carefully orchestrated series of cellular events involving inflammatory cells which must first leave the blood stream before they can interact in the injured tissue and lead to repair. In the present proposal, we intend to identify which cells can produce pro- or anti-inflammatory signals that contribute to the persistence or resolution of inflammation and those that can trigger tissue repair. We also want to characterize the time frame of implication for each one of these cells. In this proposal we will focuss more specifically on one type of immune cells, the mast cell. Our working hypothesis is that mast cells play key roles, not only in governing the inflammatory response, but also in modulating its resolution and the tissue repair phase. We will thus 1) Evaluate the importance of mast cell activation in modulating inflammatory cell invasion in muscle damage 2) Determine if mast cells help resolve inflammation through production of anti-inflammatory mediators and 3) Investigate the putative implication of mast cells in the regeneration phase of muscle healing and its mechanism of action. The model used in most cases is the injury in a hindlimb muscle of rat caused by injection of a toxic drug.