Protecting the pancreas: Compound fights fibrosis in animal model
ST. LOUIS — Saint Louis University researchers have found that a type of compound that disrupts the process that causes fibrosis (scarring) in the lungs and liver also shows promise in preventing and treating fibrosis in yet another organ, the pancreas. The research was conducted in an animal model.
Pancreatic fibrosis – or the formation of scar tissue in the pancreas – is associated with chronic pancreatitis, a progressive and debilitating illness that lacks a specific treatment. Patients who have chronic pancreatitis face an increased risk of developing diabetes and pancreatic cancer and diminished quality of life from chronic pain, malnutrition and diarrhea. Ultimately chronic pancreatitis progresses to a point where the patient needs to receive various enzymes and insulin to survive.
"Our study suggests it may be possible to develop a treatment that would at least preserve the remaining function of the pancreas by halting fibrosis. Ideally, by halting the fibrotic process, it's also possible the pancreas would have a chance to heal and possibly recover some of the lost function," said Barbara Ulmasov, Ph.D., lead author of the paper and associate research professor of gastroenterology at Saint Louis University.
Special cells in the pancreas called pancreatic stellate cells regulate the development of chronic pancreatitis. They are activated by a protein called Transforming Growth Factor Beta (TGFB), which stimulates fibrogenesis — a series of cellular actions that cause overproduction of collagen and its resulting scarring.
Scientists induced pancreatic fibrosis in a mouse model, and studied whether a compound called an integrin inhibitor would block the gene that activates TGFB, preventing the launch of the chain reaction that leads to scarring.
They found the integrin inhibitor prevented cellular activities that led to scarring and kept pancreatic fibrosis from developing in the animal model. They also found that the integrin inhibitor turned off the activation of TGFB in cultured cells.
The findings are important in helping us better understand potential prevention and treatment of pancreatic disease, said David Griggs, Ph.D., senior author and director of biology at Saint Louis University's Center for World Health and Medicine.
"Although the understanding of the causes of chronic pancreatitis and pancreatic cancer have advanced in the past decade, neither the incidence nor the outcome from these diseases has changed — indicating that large gaps in knowledge remain that have prevented the development of effective preventive and treatment measures," Griggs said.
"In this paper we identified a group of proteins as new and important players in the mechanism of pancreatic fibrogenesis. Using a mouse model of chronic pancreatitis developed in SLU's laboratory, we demonstrated that small molecular compounds developed by SLU's Center for World Health and Medicine can very rapidly arrest the fibrosis process even after it is well underway in the organ."
The next steps, Griggs said, are to study how integrin inhibitors react with other cells in the pancreas and to see if the compound, which was given to mice as an infusion, can be turned into a drug that is given orally.
The findings were published online on March 16, 2016 in a Cellular and Molecular Gastroenterology and Hepatology article in press and build upon research published in Nature Medicine in 2013.
Authors are Barbara Ulmasov, Ph.D., Brent A. Neuschwander-Tetri, M.D., Jinping Lau, M.D., Ph.D., Vladimir Monastyrskiy, Trish Bhat, Matthew P. Yates, Jonathan Oliva, Michael J. Prinsen, Peter G. Ruminski and David W. Griggs, Ph.D.
The research was funded by grants from the National Pancreas Foundation and the Frank R. Burton Memorial Fund, a fund establish to honor the memory of SLU physician and researcher who treated and studied pancreatic disease.
Ruminski and Griggs are consultants and equity holders of Antegrin Therapeutics Inc., a drug discovery and development company which was spun out of SLU's Center for World Health and Medicine. Antegrin has licensed patented technology related to the compounds used in this study, and is dedicated to commercializing novel integrin inhibitors for the treatment of fibrotic diseases. Neuschwander-Tetri has been a consultant for Nimbus Therapeutics, Bristol Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus and Scholar Rock.
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: infectious disease, liver disease, cancer, heart/lung disease, and aging and brain disorders.