An investigation into the role of selectins in the pathophysiology of sepsis and sepsis-induced acute lung injury

Ridings, Philip Charles (1997) An investigation into the role of selectins in the pathophysiology of sepsis and sepsis-induced acute lung injury. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Gram negative sepsis and its complications such as multiorgan failure remain a significant cause of morbidity and mortality in intensive care units. In recent years great advances in our knowledge of the pathophysiology of sepsis have led to novel therapies for sepsis but none have, as yet, proved effective in the clinical situation. Neutrophil sequestration into the lung and other organs during sepsis have been appreciated as a major cause of organ failure. Only recently have the mechanisms of neutrophil sequestration, controlled by adhesion molecules, been elucidated. This thesis examines the roles of a new group of adhesion molecules, the selectins, in the genesis of lung injury in a experimental model of sepsis.

Using a porcine model of sepsis and acute lung injury, this work demonstrates significant protection against the development of lung injury by treatment, prior to the onset of sepsis, with a monoclonal antibody which binds to both L-selectin and E-selectin. To further validate a role for these selectins in the pathogenesis of lung injury, the timing of expression of these two molecules during sepsis was studied using flowcytometry and immunohistochemistry. Using this data the same antibody was then administered after the onset of sepsis, at a time when L-selectin expression was minimal. Lung protection was still observed demonstrating the relative importance of each of these selectins in the genesis of lung injury.

The effect of treatment with a synthetic analogue of sialyl Lewis x, a proposed epitope for P-, E- and L-selectin was also investigated. Pretreatment with the analogue provided significant protection against lung injury whereas delayed treatment did not. As P-selectin is rapidly but briefly expressed in sepsis these experiments indicate a significant role for this third selectin in sepsis-induced lung injury.

This thesis demonstrates a significant role for the selectins in the genesis of lung injury in sepsis and also indicates a potential novel therapeutic approach for patients with this common and often lethal condition.

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