Plasminogen System and Alcoholic Pancreatitis

Summary

Principal Investigator: Aurelia Lugea
Abstract: [unreadable] DESCRIPTION (provided by applicant): Chronic pancreatitis is a devastating consequence of alcohol abuse. Despite extensive experimental work, the pathophysiology of ethanol-induced pancreatitis remains unclear. The discovery that extracellular proteolysis associated with the plasminogen (plg) system participates in tissue remodeling has led to increased recognition of the key role of this system in tissue repair in several organs. However, the role of the plg system in ethanol-induced pancreas damage remains unexplored. The broad, long-term objective of this proposal is to elucidate the participation of the plg system in the development of pancreatic fibrosis induced by ethanol. Preliminary data using mice genetically deficient in plg demonstrated that plasmin activity is required for pancreas recovery following pancreatitis. Additional experimental data from rats suggests that ethanol intake leads to inhibition of plg activation and consequent impairment of the pancreas damage recovery process. Therefore, we hypothesize that ethanol-induced alterations in the plg system are an integral part of the mechanisms underlying fibrogenesis in alcoholic pancreatitis. The specific aims of this proposal are to elucidate the role and regulation of the pancreatic plg system during tissue repair processes and the mechanisms of action of ethanol on this system in mediating pancreas fibrosis. Our approach to accomplish these aims will be to examine the course of cerulein-induced pancreatitis in mice with genetic alterations of plasminogen activator inhibitor-1 (PAI-1), the major physiologic regulator of the plg system. The experimental groups will include PAI-1 deficient mice, transgenic mice overexpressing PAI-1 and their respective wild type controls. The effects of ethanol intake will be evaluated by feeding ethanol-containing diets to these mice. Finally, whether ethanol modulates the operation of the plg system in matrix turnover will be examined in primary cultures of pancreatic stellate cells (PSC), the major ECM-depositing cells in the fibrotic pancreas. The completion of these objectives will provide insights into the participation of the plg system in the maintenance of pancreas architecture and in the pathogenesis associated with alcohol abuse. Therapeutic strategies focusing on the regulation of plg activation may be central in preventing or reverting alcohol-induced pancreas fibrosis. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-07-10 - 2009-06-30
more information: NIH RePORT

Top Publications

  1. pmc Investigating the pathobiology of alcoholic pancreatitis
    Stephen J Pandol
    Pancreatic Research Group, Department of Veterans Affairs Greater Los Angeles, University of California Los Angeles, 90073, USA
    Alcohol Clin Exp Res 35:830-7. 2011
  2. pmc Pigment epithelium-derived factor regulates early pancreatic fibrotic responses and suppresses the profibrotic cytokine thrombospondin-1
    John C Schmitz
    Section of Digestive Diseases, VA Connecticut Healthcare System, New Haven, Connecticut, USA
    Am J Pathol 179:2990-9. 2011
  3. pmc Epidemiology, risk factors, and the promotion of pancreatic cancer: role of the stellate cell
    Stephen Pandol
    Southern California Research Center for Alcoholic Liver and Pancreatic Diseases, University of California and Department of Veterans Affairs, Los Angeles, California, USA
    J Gastroenterol Hepatol 27:127-34. 2012
  4. pmc Pancreas recovery following cerulein-induced pancreatitis is impaired in plasminogen-deficient mice
    Aurelia Lugea
    USC UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California 90073, USA
    Gastroenterology 131:885-99. 2006
  5. pmc The pancreatic stellate cell: a star on the rise in pancreatic diseases
    M Bishr Omary
    Department of Medicine, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
    J Clin Invest 117:50-9. 2007

Scientific Experts

Detail Information

Publications5

  1. pmc Investigating the pathobiology of alcoholic pancreatitis
    Stephen J Pandol
    Pancreatic Research Group, Department of Veterans Affairs Greater Los Angeles, University of California Los Angeles, 90073, USA
    Alcohol Clin Exp Res 35:830-7. 2011
    ..As our understanding of alcohol's effects continue to advance to the level of molecular mechanisms, insights into potential therapeutic strategies will emerge providing opportunities for clinical benefit...
  2. pmc Pigment epithelium-derived factor regulates early pancreatic fibrotic responses and suppresses the profibrotic cytokine thrombospondin-1
    John C Schmitz
    Section of Digestive Diseases, VA Connecticut Healthcare System, New Haven, Connecticut, USA
    Am J Pathol 179:2990-9. 2011
    ..PEDF-null mice, however, demonstrated enhanced early fibrotic responses compared with wild-type mice with pancreatitis. These findings indicate that PEDF acts as a compensatory antifibrotic cytokine in pancreatitis...
  3. pmc Epidemiology, risk factors, and the promotion of pancreatic cancer: role of the stellate cell
    Stephen Pandol
    Southern California Research Center for Alcoholic Liver and Pancreatic Diseases, University of California and Department of Veterans Affairs, Los Angeles, California, USA
    J Gastroenterol Hepatol 27:127-34. 2012
    ....
  4. pmc Pancreas recovery following cerulein-induced pancreatitis is impaired in plasminogen-deficient mice
    Aurelia Lugea
    USC UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California 90073, USA
    Gastroenterology 131:885-99. 2006
    ..To understand better the role of plg in pancreas recovery following injury, we examined the course of cerulein-induced pancreatitis in plg-deficient and -sufficient mice...
  5. pmc The pancreatic stellate cell: a star on the rise in pancreatic diseases
    M Bishr Omary
    Department of Medicine, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
    J Clin Invest 117:50-9. 2007
    ..Therefore, understanding the biology of PaSCs offers potential therapeutic targets for the treatment and prevention of these diseases...