Acute pancreatitis is a sudden, severe inflammation of the pancreas which may eventually lead to life-threatening complications associated with digestive necrosis of the gland. Premature, intracellular activation of zymogens is believed to be responsible for the onset of acute pancreatitis; however, the underlying mechanisms remain unidentified. Alcohol is one of the most common risk factors in the development of this condition and may promote its deleterious effects by directly sensitizing the pancreatic acini to CCK, an important gastrointestinal peptide hormone and a digestive enzyme regulator which physiologically activates Ca2+ channels, thus serving an integral role in the physiological regulation of digestive enzyme secretion by pancreatic acinar cells. Nicotine exposure presents an accessory agonist and predisposing factor which may render the pancreas more susceptible to the injurious effects of alcohol-induced gland deficiency. It is important to evaluate the possible cumulative effect of these two high-risk factors in the pathophysiology of acute pancreatitis. The present study addresses the modulatory effects of ethanol and/or nicotine on CCK-evoked Ca2+ alterations and premature intracellular trypsin activation in murine pancreatic acinar cells. Our results indicate that alterations in Ca2+ signaling are often associated with pH modifications and may occasionally complement the conversion of trypsinogen to active trypsin in a time- and concentration dependent manner. We found corroborative evidence that ethanol affects cell signaling and sensitizes cells to the effects of CCK stimulation. Moreover, we found that the initiation of premature trypsin activity does not always succeed changes in [Ca2+]i. We also found evidence to support one existing pathophysiological theory which states that changes in [Ca2+]i are not a necessary indicator of premature trypsin activation. This initiating mechanism pathway may serve to complicate the development of therapeutic treatment and would suggest that other intrinsic factors may play a role in premature intracellular trypsin activation. These results not only indicate that CCK, ethanol and/or nicotine can trigger Ca2+ and pH responses, which may lead to autoactivation of digestive enzymes, but more importantly, may provide further evidence that Ca2+ is not the only initiating indicator of acute pancreatitis. Understanding the underlying cellular mechanism(s) by which ethanol and nicotine modulate pancreatic acinar cell activity and lead to premature intracellular activation of zymogens is paramount in design considerations which would identify pharmaceuticals effective in preventative and therapeutic treatment for acute pancreatitis. / A Dissertation submitted to the Department of Chemical and Biomedical Engineering
in partial fulfillment of the requirements for the degree of Doctor of
Philosophy. / Degree Awarded: Fall Semester, 2007. / Date of Defense: November 2, 2007. / Acinar, Trypsin / Includes bibliographical references. / Prescott Bryant Chase, Professor Directing Dissertation; Kenneth Brummel-Smith, Outside Committee Member; Egwu Kalu, Committee Member; Bruce R. Locke, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_168564 |
| Contributors | Sweeney, Nekeisha S. (authoraut), Chase, Prescott Bryant (professor directing dissertation), Brummel-Smith, Kenneth (outside committee member), Kalu, Egwu (committee member), Locke, Bruce R. (committee member), Department of Chemical and Biomedical Engineering (degree granting department), Florida State University (degree granting institution) |
| Publisher | Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text |
| Format | 1 online resource, computer, application/pdf |
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