Research on excessively “leaky” microvessels may lead to better trauma treatment
Jerome Breslin studies what happens when the endothelial barrier is breeched by traumatic injury and inflammation
Traumatic injury is the leading cause of death among people ages 1 to 44 in the United States. The body’s inflammatory response accompanying massive injury can severely complicate the resuscitation of trauma victims, worsen clinical outcomes and often lead to multiple organ failure.
In his laboratory at the USF Health Morsani College of Medicine, Jerome Breslin, PhD, and colleagues study microvascular hyperpermeability, that is, the “excessively leaky” small blood vessels that are a hallmark of systemic inflammation. Their aim is to find new, more effective ways to treat trauma and prevent early death, but their work also has implications for the treatment of lymphedema, wound healing and arteriosclerosis.
In particular, Dr. Breslin, an associate professor in the Department of Molecular Pharmacology and Physiology, looks at what happens when the protective barrier of endothelial cells forming an interface between circulating blood and tissues outside the blood vessel network is compromised by traumatic injury and inflammation.
Leaky blood vessels: The soaker hose analogy
“These capillaries are like soaker hoses used to water plants, that leak out fluid carrying proteins and other nutrients in addition to delivering oxygen to surrounding tissue,” Dr. Breslin said. “In patients who have undergone trauma or major surgery, blood pressure drops in part because the wall of the hose becomes too leaky. There is less fluid in the blood vessels and more flowing out into nearby tissues, which can cause damage and impair the function of some organs.”
In addition to investigating ways to prevent excessive blood vessel leakage, Dr. Breslin’s lab focuses on how to return the leaked fluid back into the blood by the lymphatic vessels. As a result, his team spends a lot of time studying the pumping function of the lymphatic system, which manages fluid levels in the body. Swelling, or edema, occurs when it fails to drain off excess fluid.
Dr. Breslin’s work is currently supported by two National Institutes of Health RO1 grants totaling more than $2 million.
The most recent award from the NIH’s National Institute of General Medical Sciences focuses on testing whether a class of drugs that activate the S1P1 receptor may keep blood vessels from leaking too much and stabilize blood pressure following trauma.
In this project, Dr. Breslin will use the first rat model combining alcohol intoxication and hemorrhagic shock to induce excessive leakiness in small blood vessels. He will evaluate whether fluid containing sphingosine-1-phosphate (S1P) reduces the blood vessel permeability, thereby restoring normal blood pressure and fluid balance. If so, Dr. Breslin said, drugs similar to S1P, a bioactive lipid that prevents cell death, may offer a more effective way for paramedics and physicians to resuscitate trauma patients than the standard IV fluid therapy now administered. That standard fluid resuscitation protocol works particularly poorly in alcohol-intoxicated victims suffering major blood loss, a significant portion of all trauma cases coming through emergency rooms, he said.
With the second award, a competitive renewal from the NIH’s National Heart, Blood and Lung Institute, Dr. Breslin and colleagues are studying the molecular and cellular mechanisms that may regulate and resolve microvascular leakage following inflammation caused by traumatic injury.
Unexpected finding leads to “new way of thinking”
Previous work by his group using live imaging of vascular endothelial cells under a microscope demonstrated that when the edges of these cells make contact with their neighboring cells they appear very active and are constantly remodeling, or changing shape — rapidly opening up holes at cell junctions and then closing back up. This finding, published in the journal PLOS One, countered one of the conventional theories that endothelial cells were more rigid at the junctions where they connect and adopted a contracted state during inflammation.
“It was an unexpected finding that changed our thinking about how these cells behaved,” Dr. Breslin said.
This led the researchers to begin to question the prevailing view about the role actin stress fibers — threadlike structures involved in cell stability, adhesion and movement — play in disrupting the endothelial barrier function.
Further preclinical studies by Dr. Breslin and others over several years showed that in response to an inflammatory agent actin stress fibers cause endothelial cells to spread out, not contract, at the junctions. The USF researchers published evidence in the American Journal of Physiology: Cell Physiology that actin stress fiber formation may be a reaction to, rather than a cause of, reduced integrity of the endothelial barrier that protects against excessive fluid leakage.
Earlier this year, Dr. Breslin was first author on a study appearing in the Journal of the American Heart Association showing that the signaling protein Rnd3 reduced leakage of small blood vessels when delivered a new way in a rat model of hemorrhagic shock. The researchers suggested Rnd3 (or analog drugs) might offer an anti-inflammatory treatment to repair the endothelial barrier compromised by prolonged and uncontrolled inflammation.
Live imaging of endothelial microvascular cells at 600x magnification shows the dynamic movement of the protruding cell edges (local lamellipodia). Videoclip courtesy of Jerome Breslin, PhD.
Heart Institute, former mentor a draw to USF
Dr. Breslin joined USF in 2012 from Louisiana State University Health Sciences Center in New Orleans, where he was an assistant professor of physiology. He received his PhD in pharmacology and physiology from Rutgers University – New Jersey Medical School in Newark, NJ. His postdoctoral training was conducted at both Texas A&M and the School of Medicine at the University of California Davis, where he was mentored by Sarah Yuan, MD, PhD, the chair of Molecular Pharmacology at Physiology at Morsani College of Medicine who is nationally recognized for her translational research on the regulation of microcirculation.
The opportunity to be part of a growing university, join core faculty who will help build a Heart Institute advancing bench-to-bedside cardiovascular research, and work again with Dr. Yuan attracted him to USF Health, Dr. Breslin said.
“Dr. Yuan was a great mentor to me when I was a postdoctoral fellow,” he said. “This has reopened our scientific collaborations and now we’re mentoring a student together.”
Dr. Breslin is a fellow of the American Physiological Society Cardiovascular Section and a member of The Microcirculatory Society and the American Heart Association. He is associate editor of the journal Microcirculation and a member of the editorial board of PLOS One. He has authored or co-authored nearly 40 articles in peer-reviewed journals.
Dr. Breslin serves on two NIH special emphasis panels, one on lymphatics and another for the Intramural Postdoctoral Research Associate Program. He is also a grant reviewer for the Association of American Medical Colleges (AAMC) Innovations in Research and Research Education Awards.
Something you may not know about Dr. Breslin
To help pay for tuition while earning his master’s degree in biology, Dr. Breslin worked as a park ranger in Somerset County, N.J, for a couple of summers.
No stranger to outdoor activities, including camping, as a teen Dr. Breslin attained the rank of Eagle Scout, the highest achievement in the Boy Scouting program. His connection with scouting continues today as committee chair for his 13-year-old son’s Boy Scout troop.
Dr. Breslin’s Scouting experiences included learning wilderness survival skills, such as how to build a shelter from scratch in the woods or navigating a group of boys through the wilderness without a map and compass, or a smartphone for that matter. They were instrumental, he said, in helping him develop the resourcefulness and leadership skills he hopes to impart to the emerging scientists he mentors in his laboratory
In case you’re wondering, one of the most challenging of the merit badges he earned as a Boy Scout: bugling.
Photos and audioclips by Sandra C. Roa, USF Health Communications and Marketing