Recipe For Poor Wound Healing: Bacterial Infection Plus Stress

Finding may lead to novel stem cell treatments for chronic wounds
(SACRAMENTO, Calif.) – The stress hormone epinephrine – the source of the “fight-or-flight” response – also heightens stresses at the cellular level, inhibiting wound healing and promoting a state of chronic inflammation that prohibits the body’s stem cells from migrating to a wound to encourage skin regeneration, UC Davis researchers have found. 

The research, published in the April issue of the scientific journal Stem Cells Translational Medicine, is the first to show that epinephrine cross-activates other cellular pathways that feed off each other, generating inflammatory proteins in an exaggerated response that impedes wound healing. The research has important implications for the development of new treatments for chronic nonhealing wounds, conditions that affect more than 5 million Americans. 

“We have discovered that the pathways activated by the ‘fight-or-flight’ hormone epinephrine and those activated by the presence of bacteria in wounds communicate with one another synergistically, greatly promoting inflammation,” said Mohan R. Dasu, lead author of the study and an associate researcher in the UC Davis Department of Dermatology. “The combination of stress and infection is a recipe for chronic infection.” 

Chronic infections are a major global health problem, with annual costs in the United States alone estimated to be more than $23 billion. Nonhealing wounds are particularly common in patients with diabetes, who often develop sores in the foot or leg that become chronic despite intensive antibiotic treatment and sometimes require amputation. 

While chronic wounds are traditionally treated primarily with antibiotics, the findings open the way for enhancing therapy with agents that counteract stress hormones. Recent case studies have reported that topical treatment with beta blockers – agents that block adrenergic receptors – have improved chronic skin wounds, although until now, these outcomes have not been well explained. 

“Everyone knows that stress is harmful to the body,” said Roslyn Isseroff, professor of dermatology at UC Davis and principal investigator of the study. “Our findings provide a framework for systematically developing new therapeutic strategies that could selectively regulate inflammatory responses in nonhealing wounds.” Isseroff is also chief of the dermatology service at the UC Davis-affiliated Department of Veterans Affairs Northern California Health Care System where she directs a multi-specialty wound clinic. 

Biology of a Nonhealing Wound 

Bacterial colonization produces in the body an inflammatory response mediated by “Toll-like receptors” on the cell membrane – receptors that when activated, generate interleukin 6 (IL-6), a protein that plays an important role in fighting infection. Earlier work by lead author Dasu has demonstrated that activation of these receptors can contribute to nonhealing wounds in diabetic patients. In the current work, he provides an important advance to how this pathway works in the face of stress. 

At the same time, wounds cause the release of stress hormones such as epinephrine that act on adrenergic receptors to also generate IL-6. Although IL-6 is essential to fighting infection, too much creates a state of chronic inflammation and actually impairs healing. Activation of adrenergic receptors also slows movement of the body’s stem cells that naturally migrate to a wound and promote healing and skin regeneration. 

By conducting a series of experiments on stem cells and skin cells, the investigators found that separate activation of either the adrenergic receptors or the Toll-like receptor pathways generated a moderate amount of IL-6, but when both stress and bacterial colonization occurred at the same time, the amount of IL-6 was over 40 times more than one would expect. Their experiments showed for the first time that these pathways communicate with and influence one another in a manner known as “cross-talk,” causing a highly exaggerated response. 

A term borrowed from electronics, cross-talk describes a phenomenon by which a signal transmitted on one circuit creates an effect on another circuit. In the case of the cross-talk between the two pathways in this study, a positive feedback loop is created so that signals from each pathway stimulate the other, resulting in a heightened effect. 

New Stem Cell Therapies 

 Further investigations being conducted by Isseroff’s group funded by the California Institute for Regenerative Medicine (CIRM) focus on developing a biological device involving stem cells pretreated with a beta blocker that can be used to treat chronic infections. They also intend to conduct a randomized clinical trial to apply topical beta blockers directly to wounds. 

“The effects of stress on tissue is a very novel area that not many people have studied and opens up new avenues of research,” said Jan Nolta, professor and director of the UC Davis Stem Cell program and co-principal investigator of the study. “Just like the body, tissue is harmed by stress, and regulating stress may help stem cells improve tissue healing.” 

Nolta noted that this study is an example of the fruitful partnership of UC Davis and Sacramento State University through the Bridges to Stem Cell Research Awards, funded by the California Institute for Regenerative Medicine. The program provides research opportunities at UC Davis for Sacramento State University students as part of their Masters of Art in Biological Sciences degree with a stem cell concentration. Two of the study authors, Chelcy Mashburn and Thomas Peavy, are participants in the program. 

The article is titled, “Cross talk between adrenergic and Toll-like receptors in human mesenchymal stem cells and keratinocytes: a recipe for impaired wound healing.” 

Other study authors were Sandra Ramirez, Thi Dinh La, Farzam Gorouhi, Chuong Nguyen, and Benjamin Lin, all of the UC Davis Department of Dermatology, and Heather Stewart of the UC Davis Institute for Regenerative Cures. 

The research for this study was funded by the National Institutes of Health R34 AI080604, United States Department of Veterans Affairs Merit Award, CIRM grant TR2-01787, CIRM Training Grant to UC Davis, CIRM Bridges to Stem Cell Training Grant to California State University, Sacramento, and NIH Director’s Transformative Award 1R01GM099688.