Increased matrix protein degradation products, including fibrinogen degradation products (FDPs), have been associated with the development of systemic inflammation and multiple organ failure in trauma patients. Besides a well-recognized role as biomarkers of hemostasis function, FDPs have been implicated in inflammation, pathological angiogenesis, and wound healing. A vascular permeability effect of fibrinogen and its proteolytic fragments as a whole has been reported; however, there is limited knowledge regarding specific products which function distinctively based on molecular conformations, and even less is known about their mechanisms of actions. Our recent studies have produced an interesting finding that the plasma and tissue levels of the C-terminal fragment of fibrinogen-3 (3C), a major component of FDPs, are increased in animals after severe burn. The response was coupled with systemic edema and mortality, consistent with other reports regarding correlated circulating FDP levels and severities of systemic inflammation in trauma patients. We then examined the microvascular effects of 3C and found that it directly caused hyperpermeability. These data indicate an intriguing possibility that matrix degradation products containing 3C act as pathogenic factors in vascular inflammation. The objective of this project is to define the role and molecular mechanisms of 3C- induced microvascular hyperpermeability under burn-relevant inflammatory conditions. The central hypothesis states that burn-elicited matrix degradation and fibrinolysis elevate 3C which targets the endothelial barrier and promotes plasma leak. The 3C-induced hyperpermeability occurs via integrin- coupled RhoA signal transduction leading to endothelial cell contraction and junction dissociation.
Three specific aims are proposed to 1) characterize the role of 3C in regulating microvascular permeability; 2) identify the endothelial receptor that mediates 3C-induced hyperpermeability; and 3) examine the molecular mechanisms by which 3C increases endothelial permeability. We will use complimentary approaches that incorporate molecular techniques into physiological experiments for an in-depth analysis of permeability regulation in the mesentery as representative microvasculature of the GI system, a major target of burn. Data derived from this study will provide novel, mechanistic insights into the molecular basis of barrier injury in gastrointestinal microvessels.
Systemic inflammatory injury is a major cause of mortality and morbidity in patients with severe trauma and burn. As a cardinal component of inflammation, microvascular barrier dysfunction occurs in multiple organ systems rendering plasma leak and tissue edema, which imposes a life-threatening problem to trauma patients. Development of effective therapeutic strategies requires an in-depth understanding of the end-point cellular reactions responsible for the injurious process. Currently, our knowledge regarding the molecular basis of microvascular barrier regulation is rather limited, and research in this area has been hampered by the difficulties in translating cell biology to systems pathophysiology. The proposed work is innovative not only because it has the potential to identify a new molecular pathway that mediates microvascular inflammatory injury, but because it implements novel experimental models and techniques that can integrate molecular reactions with vascular functions under clinically relevant conditions. Data derived from this study will provide new mechanistic insights into the pathophysiological regulation of microvascular barrier function. Identification of key molecules leading to microvascular leakage will assist in the development of new therapeutic targets against inflammatory injury.
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