When the pancreas heals itself

Diseases related to the pancreas, such as pancreatitis, are complex because they do not have a single initial cause. There are many mechanisms affected, which means that there are no specific treatments that medicine can apply. However, in 85% of cases it is the pancreas itself that treats and cures pancreatitis, and it does so within ten days.

In the Institute of Biochemistry and Molecular Medicine Professor Alberto Boveris (IBIMOL) of the Faculty of Pharmacy and Biochemistry of the National University of Buenos Aires (UBA), in collaboration with the National Council of Scientific and Technical Research (CONICET), in Argentina all At these institutions, a work team is dedicated to studying the mechanisms that pancreatic cells use to defend themselves against disease.

Acute pancreatitis begins when pancreatic enzymes are activated out of place and at the wrong time. They should do it when they reach the intestine, to digest the food. Instead, they do so before being secreted and within the cells that produce them, causing the tissue itself to digest and triggering a sudden and painful illness.

But if the disease is not severe, the organ returns to normal within a week to ten days. The enzymes are no longer activated, and the pancreas recovers. However, the mechanisms that the pancreas uses to heal itself are not fully understood.

“We found one of those mechanisms. It is through a protein that triggers autophagy, a process that the cell uses to get rid of unwanted material”, explained to Argentina Investiga the tenured professor at the UBA María Inés Vaccaro, director of IBIMOL and senior researcher at CONICET.

“What the protein does is detect those zymogens (inactive precursors of digestive enzymes) that are autoactivated within the pancreas at a time and place where they shouldn’t,” Vaccaro continued. “Then, the expression of this protein is activated and generates vesicles called autophagosomes, which are a kind of double-walled bags that selectively trap the activated zymogen granules. They kidnap them and lead them to degradation; the process is called autophagy. This prevents the enzyme activation from spreading throughout the pancreas and is an effective mechanism to prevent the severe form of the disease. That is, the pancreas heals itself.

The path followed by this research, which began to be made public in 2002, continued with the cover of the prestigious academic journal JBL in 2007, and also with the most famous 2011 study in the same journal and, more recently, in the academic journal Frontiers in Cell and Developmental Biology. He contributed a great deal of scientific knowledge obtained by Dr. Vaccaro’s group and by other international groups on how cells recycle unwanted material and eliminate threats to the immune system.

“We don’t know the treatment for pancreatitis, but the pancreas does,” Vaccaro explained. “So, that is where our working hypothesis begins, which consists of looking for what happens in the cells of the pancreas during the disease. What makes that cell capable of recovering the organ. It is both capable of going to severe pancreatitis and causing death, and of curing itself”.

“The severe version of the disease becomes a systemic inflammatory response. Similar to what we now describe as severe COVID. An exaggerated and generalized inflammatory response”, clarified the researcher.

Although there are currently more treatments to deal with this severe inflammatory response, if the game wins it ends in the death of the affected person. But that’s not a specific treatment for pancreatitis either, it’s a treatment for a severe inflammatory disease. “The only one who knows how to treat the pancreas is the pancreas itself. We study how it does it”, explained the scientist.

Members of the research team of the IBIMOL institute. (Photo: IBIMOL / UBA)

Like detectives searching for clues, the IBIMOL team began searching for the suspects. In this case, what genes are involved at the onset of pancreatitis, and what changes were seen in the associated cells.

In 2002, they discovered a protein called VMP1, which is expressed at the onset of acute pancreatitis, and they thought it had to be related to that cellular response to the disease. They began to study it and saw that when it was expressed, it formed vesicles inside the cell, that is, small bags that surround and usually transport materials in and out of the cell.

After years of study, they discovered that this protein, by the mere fact of expressing itself, induced what is known as autophagy, a mechanism that the cell uses to get rid of unwanted material. That study landed them the cover of the famous academic journal JBL in 2007.

“The vesicles that we discovered in 2002 that appeared when the protein was expressed were the famous autophagosomes, which are double-membrane vesicles,” Vaccaro explained. “A protein that is expressed only when the pancreas is diseased. So we thought, is it part of the disease mechanism, or is it part of the cell’s defense to rebuild and heal the pancreas?”

They found that the protein induced autophagy upon expression. But this protein is only expressed when the pancreas is sick, if it is healthy it does not appear. So, in order to study the mechanism of the disease, they had to know if it was part of it or part of the defense response of the organ cell to recompose and heal itself.

So, in collaboration with a French university, they created a transgenic mouse, in which this protein is expressed spontaneously and exclusively within the pancreas. “If the protein that we call VMP1 is part of the disease, we are going to find that the mice that express it should get sick spontaneously, developing acute pancreatitis. Because we are expressing the protein when and where it should not be expressed”, reported the researcher.

“We put a gene that was our protein fused to a green fluorescent protein. We began to study them, hoping that at any moment they would develop pancreatitis,” Vaccaro continued. “But they were phenomenal. So, we said, let’s model pancreatitis in these mice to see if they develop severe pancreatitis or mild pancreatitis.” Mice, in general, with this model become ill with severe pancreatitis, which generates necrosis. That is, the cells within the pancreas die and generate a significant inflammatory attack.

“We gave the transgenic mice the induction treatment for severe pancreatitis and we saw, surprisingly, that they almost did not get sick, and when we studied the pancreas they only had mild pancreatitis,” the scientist clarified. “The other organs were perfect, there was no systemic inflammatory response. In contrast, mice that do not express the protein in the pancreas are highly affected, developing severe pancreatitis.”

“Evidently, this protein is expressed when the disease is triggered, but not to make the disease worse, but to protect the organ,” Vaccaro explained. This was a global scientific breakthrough, which can even be applied to understanding how other diseases work, and how this housekeeping mechanism known as autophagy can be harnessed in the development of new treatment strategies.

Currently, the IBIMOL team led by María Inés Vaccaro is working to understand how to take advantage of this mechanism to finally be able to treat pancreatitis. “For now, what we are looking for is that our knowledge is applicable, that our discovery has a function,” Vaccaro concluded. “We are looking to predict if pancreatitis will be mild and self-limiting, or if it will progress to a severe and lethal form. Likewise, we seek to investigate whether this protein can be a biological marker for pancreatic diseases, since we are studying whether the vesicles of this protein have a protective function for pancreatic diseases.” (Source: Martín Cagliani / UBA / Argentina Investiga)