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Title: The role of the gut in the pathogenesis of distant organ injury during severe acute pancreatitis
Author: Mole, Damian James
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2008
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Abstract:
Multiple organ failure is the major cause of death during severe acute pancreatitis (AP), for which there is no effective prevention or treatment. Although the cause of distant organ injury is poorly understood, the clinical benefit of protecting the gastrointestinal tract through enteral nutrition implies a causative role for gut inflammation. In this thesis, the role of the gut in the pathogenesis of distant organ injury in AP was explored. It was soown that established experimental AP generates a state of diminished production of type I proinflammatory cytokines by the liver in response to portal lipopolysaccharide (LPS), and systemically in response to intra-arterial LPS. Enhanced production of the antiinflammatory cytokine IL-IO was observed. As portal LPS did not appear to cause exaggerated cytokine production in AP, the mesenteric lymph route was explored as an alternative pathway of gutderived inflammation. Mesenteric lymph duct ligation diminished AP-induced lung and erythrocyte injury. In AP, lymph became cytotoxic to endothelial cens, gut epithelial cens, erythrocytes and activated neutrophils in vitro. Mesenteric lymph from AP survivors reverted back to an inert state, and lymph from sham-operated animals remained inert throughout. Hierarchical clustering of highthroughput proteomic spectra, using surface-enhanced laser desorption ionisation time-of-f1ight mass spectrometry (SELDI-TOF MS), predicted impending cytoxicity and recovery through the differential expression of at least 100 individual proteins related to the onset of cytotoxicity. Mass spectrometry of proteins resolved by two-dimensional gel electrophoresis revealed that haptoglobin and transferrin were depleted, ai-protease inhibitor was more abundant, and apolipoprotein Al was altered in cytotoxic lymph compared to inert lymph. In conclusion, the mesenteric lymphatic pathway as a mediator of distant organ injury in AP represents a new paradigm in the understanding of the development of organ failure in AP. This work opens avenues for future research' with the potential for clinical benefit to patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Queen's University Belfast, 2008 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.485027  DOI: Not available
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