UC Davis

Stress hinders wound healing, researchers find

By From page A4 | May 15, 2014

The stress hormone epinephrine — the source of the “fight-or-flight” response — also heightens stresses at the cellular level, inhibiting wound healing, UC Davis researchers have found.

The research has potentially 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 Dasu, lead author of the study and an associate researcher in the UCD 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.

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. Until now, these outcomes have not been well explained.

“Everyone knows that stress is harmful to the body,” said Roslyn Isseroff, professor of dermatology 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.”

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, or IL-6: a protein that plays an important role in fighting infection.

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.

When both stress and bacterial colonization occurred at the same time, however, the amount of IL-6 was over 40 times more than one would expect.

Their experiments showed for the first time that these pathways influence one another in a manner known as “cross-talk.” It creates a positive feedback loop, so that signals from each pathway stimulate the other ad result in a heightened effect.

Further investigations being conducted by Isseroff’s group funded by the California Institute for Regenerative Medicine 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 UCD Stem Cell program.

“Just like the body, tissue is harmed by stress, and regulating stress may help stem cells improve tissue healing.”

— UC Davis News

Carole Gan

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