The role of fibrin degradation products in neutrophil recruitment to the lung

Pulmonary epithelial injury leads to increased permeability and plasma exudation. Plasma rapidly forms an insoluble fibrin clot in the distal airspace because of the potent procoagulant activity expressed there. Because these airspaces also express potent fibrinolytic activity, digestion of fibrin results in high local concentrations of fibrin degradation products (FDP), which are biologically important molecules with numerous proinflammatory actions. Inflammatory lung injury is associated with neutrophil accumulation, and other matrix proteins affect inflammatory cell traffic. In this study we examined the potential role of FDP in neutrophil recruitment to the lung. Using a chemotaxis assay, we found that FDP are potent chemotactic proteins when neutrophils are prestimulated with lipopolysaccharide (LPS) or formylmethionylleucylphenylalanine (fMLP). Although FDP are high molecular weight proteins, we found that these potent chemoattractants induce polymorphonuclear leukocyte (PMN) migration across epithelial monolayers. The magnitude of response is dependent upon the monolayers' ability to form and maintain tight junctions. Human neutrophil elastase (HNE), another fibrinolytic enzyme released from neutrophils, digests fibrin into chemotactic peptides which are more potent on a weight basis than plasmin-generated FDP. Furthermore, HNE secondarily digests plasmin FDP, producing molecules which are more potent chemoattractants than native plasmin FDP. These observations suggest a potential mechanism whereby FDP may contribute to the neutrophil accumulation which characterizes many inflammatory lung diseases.