Fibrin is a determinant of neutrophil sequestration in the lung.

Abstract

We investigated the role of fibrin in the sequestration of neutrophils hi lungs challenged with microembolism. Lungs of chronically prepared awake sheep were imaged after Infusion of '"In-neutrophils and ul I-fibrinogen. Thrombin (80 units/kg) was administered to induce fibrin sequestration hi the lung. One group received tranexamic add (4 mg/kg i.v.) to inhibit fibrinolysis, and the control group received a saline infusion. Thrombin infusion increased both u 'I-fibrinogen and "'In-neutrophils hi the lung, but the increases were greater and more prolonged in the fibrinolysis-inhibited group. We examined the adherence of isolated neutrophils to fibrin matrix to investigate how neutrophil-fibrin interactions could mediate neutrophil sequestration. Unstimulated neutrophils showed a 37.5 ±3.1% adherence to fibrin hi contrast to a 3.9±0.4% neutrophil adherence to endotheu'um and a 6.5±0.5% adherence to agarose. Neutrophil adherence to fibrin increased to 81.7 ±6.2% with activation by phorbol myristate acetate (10"' M) and was inhibited by a monoclonal antibody directed against the /3-chain of the CD18 leukocyte adhesion glycoprotein. The findings indicate that retention of pulmonary fibrin microthrombi is associated with increased lung uptake of neutrophils.

Feasibility of Tissue Plasminogen Activator Formulated for Pulmonary Delivery

“…We have demonstrated that tPA possesses antiinflammatory properties in addition to the well-characterized fibrinolytic activity (2,21). Taken together, the antiinflammatory and fibrinolytic activities of tPA could prove beneficial in the treatment of ARDS because the condition is associated with both an acute inflammatory response and fibrin deposition (22)(23)(24). The data presented in this study support the feasibility of formulating tPA for nebulization and pulmonary delivery.…”

Role of catalytic and lysine-binding sites in plasmin-induced neutrophil adherence to endothelium.

“…The action of plasmin in inducing neutrophil adherence is comparable in magnitude and time course to other neutrophil adhesion-promoting mediators such as C5a and FLMP, which act primarily on neutrophils (17). These agents also increase neutrophil adhesiveness over a short time (i.e., within 1 h).…”

“…The rapidity of the adherence response is compatible with increased functional activity of CD1 8 without translocation of CD1 8 glycoprotein from the cytoplasmic storage granules to the cell surface (39). The persistence of the plasmin effect for up to 30 min after washing is in contrast to effects of other mediators such as C5a (17) and LTB4 (20), which result in a rapid modulation of neutrophil adherence.…”

“…Plasmin (> 1 U/ml) induces platelet aggregation, protein phosphorylation, calcium mobilization, and activation of phospholipase C and protein kinase C in platelets (15,16). In addition, the generation of plasmin after intravascular fibrin entrapment may contribute to the vascular sequestration of neutrophils (17,18).…”

“…Inflammatory mediators (e.g., thrombin, leukotriene B4 [LTB4], tumor necrosis factor [TNF], IL 1, C5a) modulate neutrophil adhesiveness (17)(18)(19)(20)(21)(22)(23)(24)(25), which, in large part, is mediated by the cell surface glycoprotein (CD 18) on neutrophils (22,26). This conclusion is based on the findings that neutrophils obtained from patients with genetic CD1 8 deficiency do not adhere to endothelium when stimulated (26) and that MAbs directed against CD 18 prevent neutrophil adhesion to the endothelium (26).…”