Soft tissue injuries are common, often debilitating, disorders. They most frequently affect young healthy individuals and are a leading cause of time lost from the work place and the sporting field. The long term objectives of this project are to improve and enhance the management of these injuries. Our previous in vitro investigations indicate that oxygen free radicals can modulate fibroblast proliferation and may provide a rapid, sensitive mechanism for inter-cellular communication, a mechanism that can be readily modulated by pharmacological means. The free radical milieu of healing tendon will be determined by measuring the potential for xanthine oxidase mediated free radical generation, lipid peroxidation, NADPH oxidase activity, and the expression of antioxidant enzymes. A series of in vitro experiments are planned to delineate the hormetic effects of oxygen free radicals on fibroblasts cultured from both human and rat Achilles tendon and skin. We aim to gain a better understanding of the mechanisms whereby superoxide radicals are released in fibroblasts, how free radicals stimulate fibroblast proliferation and chemotaxis and the role of "endogenous" free radicals in fibroblast proliferation and chemotaxis. Sensitive, reproducible methods will be developed to test the functional performance and the mechanical properties of injured rat Achilles tendons. These methods, along with biochemical and morphological assessments, will be utilized to test agents which modify the free radical environment of healing Achilles tendons in vivo. Tumor necrosis factor alpha (TNF-alpha), an agent which both increases free radical release and enhances the cells' defence against radical damage, has already shown promise as an agent which may enhance tendon healing. We anticipate that this project will provide new and clinically relevant information on the mechanisms of tendon healing and act as a forerunner for the clinical testing of agents that will enhance soft tissue healing.