Role of Prostaglandins in Disease and Infection: David Aronoff M.D.

David Aronoff is an Assistant Professor in the Department of Internal Medicine who specializes in infectious diseases.  In general, his research focuses on the regulation of the immune system by prostaglandins.  He has a special interest in the bacterial infections of the lung and reproductive tract. This interview gives the unique research perspective of a scientist trained to be a physician.
What motivated you to conduct research on prostaglandins?  What really are prostaglandins?

I’ll answer the second question first so that it can contextualize the first question.  Prostaglandins are lipids, or fats, that we have in our body.  They could also be classified as hormones.  These are very small molecules that our cells in our body make to communicate with each other and to regulate each other’s behavior. Specifically prostaglandins are involved in a number of physiological processes such as regulating the reproductive tract, circulatory system, and functions in our brain.  It turns out that prostaglandins also regulate inflammation.  So when you or I get an infection or some other kind of inflammatory response, a lot of what drives that response are prostaglandins.  In fact, medications we take to stop some of the symptoms of inflammation like aspirin, ibuprofen, and Tylenol work by blocking the synthesis of prostaglandins.
When I was in my training to be an infectious disease doctor, I saw a lot of people with infections obviously. And one of the common themes of the people with infections was that they often had fever.  So at a pretty young time of my training, I got really interested in the phenomenon of fever.  Why we have it, whether it’s a good thing or bad thing, and why we spend so much energy trying to get rid of it in people who are sick.  I started to learn more about how our body generates fever during infection and that’s where I became familiar with prostaglandins because it turns out that when we have an infection that’s bad enough to cause fever, it’s because we are making a lot of these prostaglandins in our brain in response to the infection and those prostaglandins essentially reset our thermostat.  They tell the brain to increase our body temperature and when we take aspirin, ibuprofen or Tylenol or similar medicines to lower fever, they work by blocking the synthesis in the brain of prostaglandins.  So as I was learning about fever I was finding myself learning a lot about prostaglandins.

During my fellowship, which was part of my training to become an infection doctor, I found someone at my university that was studying some of these anti-inflammatory medications, and how they work.  Specifically he was studying Aspirin and acetaminophen (Tylenol).  Because I had been interested in the clinical problem of fever and prostaglandins and why we take these medicines to lower fever I sort of jumped on the opportunity to do research in the field.  So I did a couple of years of research in pharmacology learning about how, at a molecular level, acetaminophen or Tylenol works to block prostaglandin synthesis to lower our fever.  That two-year research experience sort of swallowed me whole in terms of the field of prostaglandins.  When I finished training I wanted to continue to work in the field that I had now become pretty familiar with and so I decided to learn more about what prostaglandins were doing, not in the brain, but locally where the sites of infections were occurring.  So if we have an infection on our finger and it gets hot, red, and swollen, much of that is due to prostaglandins.  I was interested in looking at some of the functions of prostaglandins right there at the interface between germs and the person.  My background in college was in microbiology and my clinical interest is in infectious diseases.  So it was a natural fit to study prostaglandins in the context of medical microbiology or infectious disease.

Why did you choose to study prostaglandin E2? What is significant about that specific prostaglandin?

The name “prostaglandin” refers to a pretty broad class of lipids that all vary structurally at a chemical level.  The name “prostaglandin” is an amalgam of the term prostate and gland.  These compounds were first isolated from prosthetic secretions.  It turns out that prostaglandins are formed almost by every cell in the body.  It’s very much a misnomer to call them prostaglandins and it turns out there are more than one.  They all vary structurally and some very bright people chose to name them by single alphabetical letters, sort of in the order in which they were found.  It goes through much of the alphabet.  I think it may stop around prostaglandin J.  They all do very different things.  They do what they do by binding to receptors.  The receptors that detect prostaglandins are fairly specific for whichever letter prostaglandin one is talking about.
I am interested in PGE2 because dating back to my story before, PGE2 is the prostaglandin in the brain and it is primarily responsible for driving fever.  It also turns out that it is a very potent molecule in regulating our immune cells.  Other prostaglandins (PGD2, PGI2) can also regulate our immune system.  Back when I was studying fever, I was very interested in studying PGE2. I spent a lot of time thinking about how it works since it is a major prostaglandin.  These prostaglandins, even though there are several of them, don’t all exist in equal amounts.  So sort of like, at a football game, you’re more likely to find football fans than soccer fans.  So at sites of inflammation you may find more PGE2.  Because it’s so prevalent and has so many functions in regulating our immune system I am compelled to continue to study it.  But I don’t study that one molecule exclusively, it just happens to be more of a central one.

If a better of the function of prostaglandins is attained, what implications could this have on the future of medicine? What diseases could possibly be better understood?

That’s a really helpful question because as physician and as a physician scientist, what I ultimately want to do is study problems that are important to human health and disease and reveal scientifically the answers to questions that lead to improvements in human health.  We think that prostaglandins are involved not only in health but also in a number of disease states.  Three of the larger disease states that I know prostaglandins play a central role are cardiovascular disease, cancer, and inflammation.
For example, people take aspirin daily to prevent heart attacks and strokes.  The reason that works is that there are prostaglandins (not PGE2) that cause platelets to clump and form clots.  Aspirin, by blocking the production of that particular prostaglandin, prevents platelets from clumping and prevents stroke and heart attack.  The discovery of aspirin and its use in cardiovascular medicine to prevent strokes or heart attack, or even treat heart attacks has been a game changer.

In addition prostaglandins like PGE2 have been shown to drive tumor production.  So there are some patients that take inhibitors of prostaglandins to reduce their risk of cancer. We are trying to understand the biology of that so that we could maybe develop better preventative medicines for people who are at high risk for cancer or even develop better therapies to prevent spread or reduce the size of cancers.
Anti-inflammatory medicine such as ibuprofen and acetaminophen are probably the most widely consumed medicines on the planet because they reduce the signs and symptoms of inflammation.  Some of that is not without side effect.  These medicines can hurt the kidneys, the stomach by causing ulceration, and sometimes can even cause heart attacks depending on the medicine.  But some of these medicines can be improved upon.  Some of the beneficial effects can possibly be sharpened while some of the maladaptive or bad side effects of medicines can be blunted if we knew the pharmacology or the biology a little bit better.  I think there are a lot of important science that can be learned by studying the role of lipids, including prostaglandins in infectious disease.  So the deeper we dig, the more information we get, the more medications we can develop.

What are some questions still left unanswered in your research that you are currently trying to understand?

Well there are a lot more questions that are unanswered than I have been able to answer.  Once prostaglandins tickle the surface of a cell by binding to its receptor, we don’t fully understand what happens inside that cell on a biochemical level to get it to change its behavior.  So a lot of what we work on focuses on understanding how these lipids changed the signaling systems inside of cells. There’s a lot of unanswered questions about which proteins in the cell get regulated, how they touch each other, how they communicate.  Really good research always leaves more questions than answers, although hopefully it answers questions of importance along the way.  But every good answer should be quickly followed by many better questions.

By Alex Myong, Stephanie Kraftson, Jana Pohorelsky

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