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

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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.