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

除少数营养不良性疾病外，肌腱损伤并不危及生命，但在运动和工作场所是一个非常常见的问题。在加拿大，每年有220万天的此类受伤住院治疗（加拿大信息研究所）。在美国，2001年在美国运动医学学会会议上公布的统计数据显示，肌肉骨骼疾病造成了2100万个上学日和1.47亿个工作日的损失。据估计，所有这一切每年花费2 500亿美元。因此，每年消耗300亿片NSAID片剂。这显然是社会上最被忽视的创伤之一。虽然必须提出预防性护理措施，但更好地了解肌肉组织损伤和修复背后的机制将有助于更好地管理这些损伤，并制定更具成本效益的治疗和策略。组织愈合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，然后才能在受伤的组织中相互作用并导致修复。在本提案中，我们打算确定哪些细胞可以产生促炎或抗炎信号，这些信号有助于炎症的持续或消退，以及那些可以触发组织修复的信号。我们还想描述这些细胞中每一个的时间框架。在这个建议中，我们将更具体地关注一种类型的免疫细胞，肥大细胞。我们的工作假设是，肥大细胞发挥关键作用，不仅在管理炎症反应，而且在调节其解决和组织修复阶段。因此，我们将1）评估肥大细胞活化在调节肌肉损伤中炎性细胞侵袭中的重要性2）确定肥大细胞是否通过产生抗炎介质来帮助解决炎症和3）研究肥大细胞在肌肉愈合的再生阶段中的假定含义及其作用机制。大多数情况下使用的模型是通过注射毒性药物引起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.