Periods of extreme heat often result in an increase in deaths, mostly related to heart conditions. A UofL research study shows that heat also can impair the immune system and increase damaging inflammation, according to Daniel Riggs, assistant professor of environmental medicine and affiliated with .

Riggs and his colleagues recorded levels of immune cells and biomarkers in the blood of 624 participants in Louisville during summer months. They then compared those levels with the Universal Thermal Climate Index for that day, which factors in air temperature, relative humidity, wind speed and ultraviolet radiation levels as a measure of heat exposure.

They found that when it was hotter, the participants had higher levels of immune molecules in their blood, indicating a general immune response and inflammation, as well as lower levels of B-cells, which allow the body to fight specific infections. This means that with higher heat, people may be more susceptible to infection and more sensitive to environmental exposures, which in turn can contribute to worsened heart disease.

“We know that certain changes in the immune system and increased inflammation are a leading mechanism in many types of cardiovascular disease. Our findings suggest that heat exposure could be contributing to these processes that ultimately lead to greater risk of cardiovascular disease,” Riggs said.

Riggs presented at the American Heart Association Epidemiology, Prevention, Lifestyle and Cardiometabolic Health Conference in March.

The work targets a leading delivery method for the therapies, adeno-associated virus (AAV), and recently was published in the journal by UofL’s Maureen A. McCall and her colleagues from Harvard University and its Wyss Institute.

AAV is used in treating a number of conditions, including the retinal diseases McCall studies at UofL. However, it also has been known to cause serious side effects, such as elevated immune response and inflammation.

“It’s a real problem since there’s no real control,” said McCall, the Kentucky Lions Eye Research Endowed Chair and a professor in the Departments of Ophthalmology and Visual Sciences and Anatomical Sciences and Neurobiology. “Even with the best-laid plans, you see some inflammatory retinal response, and the amount can vary widely, including dangerous levels.”

The new research focuses on the role of the viral capsid, a component in AAV that’s believed to cause this response. Parts of the viral capsid interact with a protein known as Toll-like receptor 9 (TLR9), which senses foreign DNA in the body. TLR9 triggers the immune response, which causes inflammation and can reduce or eliminate the therapy’s effects.

“So, the hypothesis was that if you could change that capsid code and mask it from the Toll-like receptor, that you could build a better delivery tool,” McCall said.

The idea is to “cloak” the deleterious part of the capsid with a series of synthetic DNA “inflammation-inhibiting oligonucleotide” sequences meant to stop TLR9’s reaction. In mouse models, the researchers saw a 95% reduction in inflammation.

In many cases, gene therapies for optical diseases are delivered through the retina since the blood-retina barrier helps to mitigate some of the immune response. Ying Kai Chan, a former postdoctoral fellow in George Church’s group at the Wyss Institute, reached out to McCall in 2018 to partner on this work because of her research expertise and the experience of her UofL colleagues with these injections, especially Wei Wang, assistant professor of ophthalmology.

McCall’s work at UofL specifically focuses on the use of gene therapies to treat retinal diseases, including retinitis pigmentosa and other conditions that eventually can cause blindness. For some of these conditions, there is no known cure and many therapies are still in development and clinical trials. McCall said eliminating side effects associated with AAV delivery gets researchers one step closer to successful treatment.

“Solving this key problem with delivery is huge,” she said. “These therapies show promise in significantly increasing people’s quality of life. My hope is that one day we can use these therapies to slow – or even stop – the progression of these diseases and restore sight.”

Thanks to a pledge of $1.05 million throughout five years from the GSG III Foundation Inc., the UofL School of Medicine will create the Gibbs Lung Research Program at the Cardiovascular Innovation Institute (CII). The program will use established research and existing partnerships at CII to develop improved methods for studying diseased lungs and to explore new treatments for inflammatory lung disease.

“Given the number of people in Louisville and Kentucky who suffer from lung diseases, from COPD to cystic fibrosis to asthma, we are happy to support the community by creating a program that can ultimately lead to life-changing therapies for the people of Louisville and across the United States,” said George Gibbs, chair of the GSG III Foundation, which is based in Louisville.

Lung disease is the third leading cause of death in the United States, with chronic obstructive pulmonary disease (COPD) alone affecting 13.5 million people. Inflammation of the lungs is often the first sign of more serious lung disease. However, scientists have limited methods for studying inflammation in lungs to better understand how and why it occurs and to develop treatments.

“Other than lung cancer, most people do not understand the extent of the problem of lung disease,” said Laman Gray Jr., MD, executive and medical director of the CII. “Inflammatory lung diseases are debilitating and affect millions of individuals. What is worse is the scientific world has limited capabilities for studying these diseases. This gift from the GSG III Foundation will allow us to develop expanded modeling opportunities with the goal of reducing human suffering from lung disease.”

More than 70 percent of donor lungs are unusable for transplant. Support from University of Louisville Hospital and Jewish Hospital, both part of KentuckyOne Health, will enable the program’s investigators to obtain donated human lungs that cannot be used for transplant. Researchers in the new program plan to develop techniques to sustain these donor lungs over a longer period of time, allowing them to study the causes of inflammation as well as test potential therapies.

The goals for the program are three-part:

1. Establish an ex vivo human lung model allowing lungs that are unsuitable for transplant to be brought to CII for research. The donated lungs will be enclosed in a sterile plastic dome, attached to a ventilator, pump and filters. The lungs will be maintained at normal body temperature and treated with a bloodless solution containing nutrients, proteins and oxygen.
2. Develop methods for long-term support of the ex vivo lungs. Current processes enable the lungs to be supported for up to 12 hours, which is long enough to transport them for transplant, but not long enough for meaningful study.
3. Once these techniques are in place, researchers in the program intend to use the research models explore areas of potential benefit, including:

• Cell therapy – Explore the use of stem and regenerative cells isolated from a patient’s own fat tissue to treat lung inflammation.
• Mechanics – Develop improved methods of respiratory support by studying the biomechanics of diseased lungs and the benefits of ex-vivo lung perfusion, a method of strengthening lungs outside the body.
• Gene expression – Understand the course of dysfunction and dysregulation among the more than 40 different cell types within the lung and profile the functional changes that occur in diseased lungs and compare the gene expression to healthy lungs.

The program’s investigators will include Gray, James B. Hoying, PhD, division chief, cardiovascular therapeutics, Stuart K. Williams, PhD, division chief, bioficial organs, George Pantalos, PhD, professor of surgery and bioengineering, Victor van Berkel, MD, cardiovascular and thoracic surgeon, and Shizuka Uchida, PhD, associate professor of medicine, all of UofL.

UofL researchers hope the Gibbs Lung Research Program ultimately will become a comprehensive lung research program, leading to valuable treatments that will slow or reverse the course of lung disease, improving quality of life for millions of people.