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Title: Characterization of lung and systemic immune response throughout the disease process of severe acute pancreatitis
Author: Yip, Vincent Sui Kwong
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2012
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Acute pancreatitis is an acute inflammatory process of the pancreas, with variable involvement of other local and remote organs. There are similarities in terms of clinical presentations and manifestations between acute pancreatitis and sepsis. Recent theories from sepsis studies suggested that there is a pro-inflammatory response at the beginning and a subsequent anti-inflammatory response at a later stage of the disease. It has been proposed that it is the uncontrolled pro-inflammatory response which leads to multiorgan dysfunction; whereas the later anti-inflammatory response contributes to an immuno-compromised state, and therefore increases the likelihood for nosocomial infection. The main aim of this project is therefore to characterise the dynamics of the pro- and anti-inflammatory responses during an episode of severe acute pancreatitis, using both lung and peripheral blood as the surrogate markers for remote organ and systemic immune responses respectively during the disease process. Arginine- and caerulein- induced acute pancreatitis rodent models were used to investigate the immune responses. Although there was a trend of more severe acute pancreatitis in the arginine model than the caerulein model, there was no statistical difference in the histological scorings of both acute pancreatitis models. The present studies therefore suggest that: There was a trend of increased alveolar macrophage phagocytic capacity halfway through the disease process. However, the alveolar macrophage phagocytosis was only significantly elevated when the rodents had completely recovered from the episode of severe acute pancreatitis; The overall phagocytic capacities of both monocytes and granulocytes were significantly dampened halfway through the disease process. Granulocytes contributed to the majority of this dampening effect. At the same studied time-point, further analysis on the survival of granulocytes revealed a reduction of apoptosis/necrosis of granulocytes. These observations would therefore suggest a malfunction of bacterial clearance by granulocytes, despite their increased survival. The reason for this malfunction is uncertain. In a similar manner to the alveolar macrophages, monocyte phagocytosis was significantly upregulated in rodents with pancreatitis towards the resolution of the acute pancreatitis episode. Using lipopolysaccharides (LPS) to simulate septic events at different stages of acute pancreatitis in this rodent model, there was a net reduction in granulocyte and monocyte apoptosis halfway through the disease process, but not at any other time-points during an episode of severe acute pancreatitis. This phenomenon suggested that sepsis exerts its most profound effects on leukocyte survival halfway through the recovery from acute pancreatitis, and that this coincided with the reduction in the ability to perform bacterial clearance. In addition, the immune response in the liver, as another remote organ target, during acute pancreatitis was investigated. It was discovered that HO-1 (an anti-oxidant and heat shock protein) was induced within the liver parenchyma at the beginning of the disease process. Its reduction throughout the acute inflammatory process was associated with an increase in oxidation within the liver parenchyma. The results are discussed in the light of current knowledge on the pathophysiology of acute pancreatitis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available