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Hallie Dolin, Ph.D student, Laboratory work points to progress against sepsis | Special to The Blade

| SPECIAL TO THE BLADE
PUBLISHED ON Aug. 6, 2018

What do smallpox, the 1918 flu, and that infected cat scratch on your hand all have in common?

Your first thought is that all of them probably hurt, which is true. But the answer I’m looking for is that they’re all the result of inflammation in your body. While you might think of inflammation as a bad thing, it’s a normal process that is needed to fight off disease. The danger comes when normal inflammation spirals out of control.

Hallie Dolin
UNIVERSITY OF TOLEDO

Nearly 2,000 years ago, the doctor Celsus identified the four primary signs of inflammation as redness, swelling, heat, and pain. Those signs come from the release of molecules that rev up the body’s response to what it recognizes as foreign. You’ve most likely heard of sepsis, but probably are not aware of how it works.

Sepsis is usually caused by bacteria, which are tiny organisms that can only be seen through a microscope. Imagine you are a cell of E. coli, which is a very common infectious bacterium (the single form of ‘bacteria’). You’ve been left on a sharp surface, and so when someone accidentally cuts themselves deep enough to bleed, you and your fellow bacteria dive right in to feed and multiply. What you don’t know is that this person’s body knows you and your fellow bacteria are there, and it’s already sent an army after you.

As a common bacterium, you cannot hide from our immune system. You have molecules on your surface that our bodies have evolved to recognize over millions of years. Our cells, which you touched as you dived in, and our blood cells, touched your bacterial surface molecules and recognized you. Our cells have already set off an alarm. As you swim in the blood, proteins called cytokines, which trigger our inflammatory process, are running around our body to trigger alarms about your invasion. Our blood vessels around you are tightening and forming blood clots so you can’t move. Our blood itself is getting hotter and hotter as fever sets in, and as you look around, the white blood cells we sent out have come to swallow you whole.

You will probably die. However, in almost a third of cases of serious blood infection, so will the body you have infected.

Sepsis involves a serious infection in the bloodstream, and we have known about it for all of recorded history. We can track the proteins that make sepsis so dangerous, and recreate it in the lab. But for all that, over 700,000 cases occur every year in the United States, and over 200,000 are fatal. Why? Because the body’s inflammatory response isn’t specific to the invading bacteria.

The same inflammation that can kill bacteria so well can also damage our own organs so badly that they completely fail. This is the fatal side effect when our inflammatory responses spin out of control. Surviving sepsis also leaves people at risk of secondary infections like pneumonia, since all anti-inflammatory resources have been used up during the sepsis response.

Current treatment for sepsis is mostly supportive care, such as fluids and blood-pressure monitoring, combined with a lot of antibiotics. I study sepsis treatment as a member of Dr. Kevin Pan’s lab, in the Department of Medical Microbiology and Immunology at the University of Toledo. Our focus is the development of more effective anti-inflammatory treatments that curb out-of-control inflammatory responses.

We look at protective molecules in the blood that are responsible for ending inflammation after the bacteria aren’t dangerous any longer. Sepsis is deadly because the inflammatory response triggered by sepsis doesn’t respond to normal amounts of these anti-inflammatory proteins. My research involves telling the body to make more of these protective proteins to guard against destructive inflammation.

Specifically, I’m investigating a molecule called MAP kinase phosphatase 1, which acts as a brake for one of the most dangerous pathways of inflammation.

For the past two years, I’ve established an experimental test system for cells and animal models. I grow white blood cells from human and mouse cell lines in tissue culture plates, then add a chemical that triggers a sepsis response and a drug that we’ve found can increase the levels of MAP kinase phosphatase 1. Then I measure the response to these treatments to see how well the experimental procedure is working.

I also inject mouse models with the sepsis-inducing molecule, followed by drugs to increase levels of MAP kinase phosphatase 1. I then monitor the responses over several days to see if the mouse models remain alive, and how healthy they are.

We have promising results. Cells in culture that receive sepsis-inducing chemical along with the experimental anti-inflammatory drug make smaller amounts of inflammatory protein and look much healthier on a molecular level. The mouse models survive longer and their organs are healthier, which indicates a lower risk for medical complications.

Based on these results, our lab is working on a potential treatment for sepsis that might work better than current standard care. This treatment approach could help prevent the creation of antibiotic-resistant bacteria as well as treating sepsis, and could make the hospital safer for sepsis patients and all other patients.

Sepsis is dangerous, but I believe that we can fight it, and what we’ve seen in the lab so far indicates that better outcomes are possible.

Hallie Dolin is an M.D./ Ph.D. student in the Department of Medical Microbiology and Immunology in The University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Hallie is doing her research in the laboratory of Dr. Kevin Pan. For more information, contact Hallie.Dolin@rockets.utoledo.edu or go to utoledo.edu/med/grad/biomedical.

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