| dc.description.abstract | Severe injury is a leading cause of death and disability worldwide, affecting over 3 million individuals in the U.S. yearly. Early complications of severe injury include bleeding, thrombosis and organ dysfunction, and if they survive, these patients often experience later complications of tissue repair, including fibrosis and soft tissue calcification. Studies have suggested that a dysregulation in the body’s response to injury, the acute phase response (APR), plays a role in these complications, but the key molecular mechanisms remain elusive, making it difficult to treat patients with severe injuries. In a physiologic APR that follows a minor injury, clotting and inflammation are activated to prevent bleeding and infection, and once the injury is contained, tissue repair is activated at the site of injury to stimulate cellular repair and promote tissue remodeling. Following a severe injury, such as a severe burn, the APR becomes dysregulated, provoking complications throughout recovery. The enzyme plasmin, which degrades fibrin clots, plays a critical role in the repair phase of the APR, making it essential for proper healing of all tissues. During a pathologic APR, rather than being activated at the site of damage during tissue repair, plasmin is systemically activated early during the clotting and inflammatory response. In my dissertation, I have investigated the pathologic changes in plasmin activity following a severe injury in both human and animal models, examining the effects of early, pathologic plasmin activation on injury-induced inflammation and the consequences of poor plasmin activity during tissue repair following severe injury. The results of this work support that altered plasmin activity following severe injury provokes complications on a continuum: early, excess plasmin activity provoked by injury not only drives bleeding but also inflammation, a key instigator of organ dysfunction and thrombosis in severely injured patients, and poor plasmin activity later during tissue repair provokes calcification of injured muscle. Therefore, plasmin exerts paradoxical effects throughout convalescence following severe injury, suggesting that early inhibition of plasmin and later enhancement of plasmin activity may represent viable therapeutic approaches to reduce the risk of severe injury complications. | |
