The macrophage system or reticuloendothelial system (RES) is important to host defense against trauma, burn, sepsis, and intravascular coagulation. Plasma fibronectin is identical to cold-insoluble globulin or opsonic Alpha2 glycoprotein. It has domains with high affinity for denatured collagen, fibrin, actin, certain bacteria, and injured tissues. Plasma fibronectin is an opsonic protein which augments macrophage phagocytic clearance of nonbacterial particulates such as collagenous debris, cytoskeletal debris, and products of intravascular coagulation and sepsis. Plasma fibronectin deficiency exists in patients early after major surgery, trauma and burn and is often further depressed with sepsis post-trauma. Post-trauma pulmonary insufficiency may be, in part, mediated by lung microembolization and vascular injury due to the co-existence of RES depression, increased blood-borne nonbacterial particulates and pulmonary leukostasis. Reversal of this opsonic deficiency in patients can be accomplished by infusion of purified fibronectin or fibronectin-rich plasma cryoprecipitate. Our goal is to define the importance of plasma fibronectin deficiency and RES phagocytic failure in the etiology of multiple organ failure during sepsis following trauma or burn. We hypothesize that plasma fibronectin deficiency contributes to RES phagocytic depression after trauma. Since plasma fibronectin incorporates into the lung adhesive """"""""tissue fibronectin"""""""" pool, disturbances of fibronectin may also alter lung vascular permeability. This interdisciplinary project will investigate the: 1) influence of surgical trauma and burn with or without sepsis on plasma fibronectin, opsonic activity and RES function; 2) mechanism of restoration of plasma fibronectin after injury and influence of burn and surgery with or without sepsis on plasma fibronectin synthesis; 3) influence of sepsis and injury on clearance kinetics and tissue distribution of plasma fibronectin as well as lung tissue content of extractable fibronectin; 4) effect of activated leukocytes on fragmentation of matrix fibronectin and endothelial cell adhesion in vitro; 5) opsonic activity of fibronectin produced by endothelial cells, Kupffer cells, and hepatocytes; 6) influence of plasma fibronectin on RES function and survival during sepsis after surgery or burn in rats; 7) influence of therapy with human plasma fibronectin on RE function and lung transvascular protein clearance in sheep during post-operative sepsis; and 8) influence of fibronectin-rich cryoprecipitate on organ function in septic trauma and burn patients. Our long-range goal is to improve the treatment of organ failure in septic burn and trauma patients.
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