Welbourn, Charles Richard Burkewood; (1991) Neutrophil-endothelial interactions in ischaemia-reperfusion injury. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Ischaemia is a common clinical event leading to both local and remote tissue injury. Evidence suggests that the injury results mainly from subsequent reperfusion which causes activated neutrophils to migrate into the reperfused tissue and sequester in the lungs, inducing permeability and oedema. This thesis examines the mechanisms by which neutrophils are recruited into reperfused tissue and accumulate in the lungs, and the means by which they then induce injury. Rabbits or rats were subjected to 3 or 4 hours of bilateral hindlimb tourniquet ischaemia. When the tourniquets were released there was peripheral neutropenia, due to the microvascular adhesion of neutrophils. A chemotactic factor was generated in plasma which was identified as leukotriene (LT) B4. The plasma was capable of inducing neutrophil diapedesis which, like the neutropenia, was dependent upon the CD 18 complex of neutrophil adhesive glycoproteins. The mechanism of both the neutropenia and the diapedesis was probably a change in the conformation of existing cell surface CD 18, because there was no increase in its quantitative cell surface expression. Following reperfusion, neutrophils were sequestered locally in skeletal muscle and also in the lungs, where they induced permeability and oedema. Moreover, LTB4 was also generated in bronchoalveolar lavage fluid. Neutrophils induced lung injury via a CD 18-dependent mechanism involving elastase and reactive oxygen metabolites. Since the time course of sequestration of neutrophils in the lungs suggested that endothelium was activated directly by tumour necrosis factor-α (TNF), evidence for involvement of this cytokine was sought. TNF was identified in plasma in some, but not all, ischaemic and reperfused rats. Use of polyclonal anti-TNF anti-serum reduced the lung injury. Infusion of TNF induces a similar lung injury, and this suggests a mechanism whereby the lung is a target for reperfusion injury following hindlimb ischaemia.

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