Neutrophil-endothelial Adhesion Research Articles

Mechanisms of lung vascular injury and edema induced by pulmonary microembolism

Pulmonary vascular injury in adult respiratory distress syndrome is a multifactorial process. Activation of the clotting cascade during sepsis or tissue injury deposits fibrin microthrombi in pulmonary vessels. The fibrin clots act as a ‘sink’ for the residual α-thrombin and other clotting factors. Fibrin-induced plasminogen activation activates the complement system, resulting in the formation of neutrophil-activating peptides (C5a), which contribute to neutrophil sequestration in pulmonary microvessels. In addition, α-thrombin promotes neutrophil-endothelial adherence by effects on the endothelial cell. Macrophages may enhance increased vascular permeability by the secretion of monokines (TNF and IL-1) and lead to the recruitment and activation of neutrophils. The sequestration of neutrophils in the lung and the generation of toxic oxygen radicals and proteases in close proximity to the endothelial cell are the ultimate mediators of endothelial cell injury and increased vascular permeability.

Rapid induction of neutrophil-endothelial adhesion by endothelial complement fixation.

The adhesion of neutrophils to vascular endothelium is an early event in their recruitment into acute inflammatory lesions. In evaluating potential neutrophil-endothelial adhesive mechanisms in acute inflammation, important considerations are that adhesion in vivo may occur very rapidly following injury and that the specificity of the reaction resides in altered endothelium. That is, neutrophils adhere only to altered endothelium adjacent to an inflammatory focus, rather than at random as would be expected if activation of neutrophils were the initiator of adhesion. We have explored a possible bridging role for complement in causing early neutrophil-endothelial cell adhesion. The complement system is involved in inflammatory processes, is capable of rapid amplification, and endothelial complement fixation at sites of inflammation could generate an endothelium-restricted signal for neutrophil adhesion. We have now developed a model in which this can be investigated without complicating factors such as immunoglobulin deposition, by constructing a novel molecule, a hybrid of the endothelial binding lectin Ulex europaeus I and of the complement activator cobra venom factor. This molecule has the capacity to cause fixation of complement on human umbilical vein endothelial cells. We show that complement fixation is a potent and rapid stimulus for neutrophil adhesion. Neutrophil adhesion requires only endothelial deposition of C3, and is mediated through the type 3 complement receptor.

Monoclonal 904 (F(ab′) 2 binds leukocyte Mo1 receptor preventing neutrophil endothelial adhesion during canine coronary artery thrombosis: JK Mickelson, PJ Simpson, M Cronin, PT Hoff, JW Homeister, KA Lee, RF Todd, BR Lucchesi. The University of Michigan, Ann Arbor, Michigan

Monoclonal 904 (F(ab′) 2 binds leukocyte Mo1 receptor preventing neutrophil endothelial adhesion during canine coronary artery thrombosis: JK Mickelson, PJ Simpson, M Cronin, PT Hoff, JW Homeister, KA Lee, RF Todd, BR Lucchesi. The University of Michigan, Ann Arbor, Michigan