| Summary: | In spite of improvements in the care of the critically ill patient, both elective and emergency vascular surgical interventions are associated with significant morbidity and mortality. Successful reperfusion of the ischaemic limb often initiates a systemic inflammatory response syndrome (SIRS), which may be complicated by multiple organ failure, including Acute Lung Injury (All) and the Acute Respiratory Distress Syndrome (ARDS). An exaggerated inflammatory response has been shown to play an integral role in the development of ARDS following lower torso or limb ischaemia-reperfusion injury. JNK enzymes, part of the Mitogen Activated Protein Kinase (MAPK) group, have been implicated in neutrophil activation as part of this response. Furthermore the role of JNK in ischaemia reperfusion injury is well established .as well as its role in All as evidenced by the attenuation of such injury with inhibitors in a number of animal models of direct lung injury. This thesis tests the hypothesis that .hibition of JNK attenuates the neutrophil-based All and ARDS associated with lower limb ischaemia-reperfusion injury. A murine model of bilateral hindlimb ischaemia-reperfusion injury was established. Lung injury was confirmed by tissue oedema, neutrophil sequestration and microvascular permeability in association with increased expression of the JNK enzymes. In a genetic JNK knockout model subjected to ischaemia-reperfusion injury, there was an attenuated lung injury as evidenced by a reduction in histology injury scores and myeloperoxidase levels. In a therapeutic inhibitor model, using the JNK inhibitor SP600125, this attenuation was observed in the histology injury scores and bronchoalveolar lavage (BAL) protein levels. These results suggest that JNK may play a role in the pathogenesis of lung injury following ischaemia-reperfusion injury and its inhibition may provide a novel therapeutic approach.
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