Plasma fibronectin is important to hepatic phagocytic function as well as lung vascular permeability. Plasma fibronectin declines in patients early after major surgery, trauma, and burn with a second prolonged phase of plasma fibronectin deficiency often observed if such patients become septic. Plasma fibronectin enhances hepatic phagocytic removal of blood-borne collagenous debris as well as products of intravascular coagulation and tissue injury. In tissue matrices, fibronectin influences cell-cell interaction and cell adhesion to a collagen-rich substratum. Plasma fibronectin can incorporate into the subendothelial matrix of the lung where its adhesive properties may influence pulmonary endothelial integrity. Matrix incorporation can be blocked by treating plasma fibronectin with N-ethyl maleimide (NEM). Fibronectin in the matrix is a mixture of both locally synthesized ED-rich cellular fibronectin and plasma-derived fibronectin. Plasma fibronectin is antigenically related to insoluble tissue (cellular) fibronectin (cFn) in the extracellular matrix, but cFn has extra domains (ED) not found in plasma fibronectin. Fibronectin in the matrix of cultured endothelial cells can be disrupted and/or proteolytically degraded by proteases such as leukocyte elastase from activated neutrophils, resulting in altered endothelial cell adhesion. We documented that plasma fibronectin deficiency amplifies the increase in lung vascular permeability in sheep during post-operative bacteremia and that infusion of purified human plasma fibronectin to maintain elevated levels can prevent this increase in permeability. We believe a balance exists between plasma fibronectin mediated hepatic phagocytic function and the level of blood-borne non-bacterial collagenous or microparticulate debris, whose inefficient hepatic removal can contribute to leukostasis and microembolic lung vascular injury. We hypothesize that plasma is a """"""""reservoir"""""""" for soluble fibronectin which can be rapidly incorporated into the lung matrix, especially during periods of vascular injury, as a mechanism to stabilize lung endothelial integrity. Since NEM-treated fibronectin cannot incorporate into the matrix but does enhance hepatic phagocytosis, we will use normal plasma fibronectin and NEM-treated plasma fibronectin to determine if this protection is mediated by either: a) fibronectin's """"""""opsonic support"""""""" of hepatic phagocytic function; and/or b) its ability to rapidly incorporate into the lung matrix where its """"""""adhesive role"""""""" can maintain endothelial integrity. Parallel studies will include the comparative effect of normal or NEM-treated fibronectin on both the permeability of lung endothelial monolayers exposed to tumor necrosis factor as well as the hepatic removal of blood-borne particulate or soluble collagenous debris. We will also determine if ED containing fibronectin as well as fibronectin fragments are released into the plasma and lung lymph of sheep during post-operative bacteremia, into the perfusate of isolated lungs during neutrophil-mediated vascular injury; as well as into the culture medium of tumor necrosis factor treated lung endothelial monolayers. This project will clarify the relationship of plasma fibronectin to both hepatic phagocytic host defense as well as lung vascular integrity.
Showing the most recent 10 out of 58 publications
