Fibrin is a determinant of neutrophil sequestration in the lung

Abstract

We investigated the role of fibrin in the sequestration of neutrophils in lungs challenged with microembolism. Lungs of chronically prepared awake sheep were imaged after infusion of 111In-neutrophils and 131I-fibrinogen. Thrombin (80 units/kg) was administered to induce fibrin sequestration in the lung. One group received tranexamic acid (4 mg/kg i.v.) to inhibit fibrinolysis, and the control group received a saline infusion. Thrombin infusion increased both 131I-fibrinogen and 111In-neutrophils in 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 in contrast to a 3.9 +/- 0.4% neutrophil adherence to endothelium 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(-8) M) and was inhibited by a monoclonal antibody directed against the beta-chain of the CD18 leukocyte adhesion glycoprotein. The findings indicate that retention of pulmonary fibrin microthrombi is associated with increased lung uptake of neutrophils. Fibrin serves as a substrate for neutrophil adherence, and this adherence is mediated by expression of the CD18 glycoprotein complex on neutrophils. Fibrin sequestration in the lung may contribute to lung vascular injury by inducing pulmonary neutrophil uptake.