Acute inflammation of the gallbladder (cholecystitis) is a serious disease which can cause substantial morbidity and death. The most significant mortality is reported in diabetic patients (10- 15%) and in patients developing acalculous cholecystitis following trauma or sepsis (40-70%). Acute acalculous cholecystitis represents 4-8% of the 500,000 cholecystectomies performed each year. The exact mechanism of acute gallbladder inflammation is not well known and thus not amenable to medical therapy a this time. Arachidonic acid metabolites have been implicated in all areas of animal gallbladder physiology by in vitro studies. These studies include water transport, mucin production, gallbladder contraction and gallstone formation.
The specific aims of this proposal are: a) to delineate the relationship of acute inflammation of the gallbladder with alterations in animal gallbladder eicosanoid production; b) the effect of these changes on in vitro water transport, and c) to determine the role of invading macrophages and fibroblasts in the changes found in gallbladder eicosanoid production. This approach will define the biochemical changes in arachidonic acid metabolism in subcellular membrane fractions and whole tissue induced by inflammation and the effect of specific inhibitors of prostaglandin and leukotriene production on these changes. Eicosanoids will be analyzed by radiochromatography and reversed phase high pressure liquid chromatography and RIA. The role of invading macrophages and fibroblasts as the source for changes in eicosanoid production will be studied by cell culture and light and transmission electron microscopy. Eicosanoid production of the inflammatory cells will be analyzed by radioimmunoassay and the chromatography techniques mentioned above. The long term goals of these studies are two fold. First, to determine why biliary obstruction leads to in-migration of inflammatory cells and the release of arachidonic acid metabolites in the early stages of acute cholecystitis. Second, to establish treatment stratagies to prevent or lessen the impact of these early events.
| Munshi, Raj; Johnson, Ali; Siew, Edward D et al. (2011) MCP-1 gene activation marks acute kidney injury. J Am Soc Nephrol 22:165-75 |
