Epigenetics and Biochemistry of Stress in Wound Care

Wound care can be a surprisingly emotional field. Some days it can feel like every patient visit contains challenging emotional situations that clinicians must also recover from with resilience not to carry that energy to the next visit. These stressors can be related to the patient’s medical status and critical conversations regarding their health, pain and anxiety, the death of a patient’s close family members, and even access to basic necessities like safe housing and social support. Factors other than the health care they receive are driving outcomes, consistent with what we know about social determinants of health which determine 80% of health outcomes.¹ These life stressors and the stressors that have occurred throughout the patient’s life can contribute to physiologic changes that further delay wound healing.

Adverse childhood events (ACEs) are one form of life stressors that significantly impact future health outcomes. These childhood events include neglect, experiencing or witnessing violence, having a family member attempt or die by suicide, chronic exposure to caretakers with substance abuse and mental health issues, and household instability such as having a parent in prison or losing a parent to separation or divorce. Identifying as LGBTQ or a person of color (POC) significantly increases the likelihood of experiencing one or more ACE. Adverse childhood events are extremely common, with 61% of adults reporting experiencing at least one type of ACE and one in six reporting four or more types.²

Exposure to ACEs predisposes children to social and emotional disorders and physical illness.³ Trauma in childhood can be incredibly impactful due to rapid brain development and a lack of context for their experiences. Adverse childhood events have been linked with several chronic diseases, including autoimmune diseases,⁴ cancer,⁵ chronic obstructive pulmonary disease,⁶ ischemic heart disease,⁷ and mental health disorders such as depression, hallucinations, and somatic disorders.² The increased risk of cancer associated with ACEs is also associated with increased lifetime exposure to modifiable cancer risk factors that also include genetic and epigenetic components: including alcohol use, environmental carcinogens, chronic inflammation, sex hormones, immunosuppression, infectious agents, obesity, radiation, ultraviolet (UV) radiation, and tobacco use.5 Preventing ACEs could significantly reduce disease burden; researchers believe preventing ACEs could prevent up to 1.9 million cases of heart disease and 21 million cases of depression.²

Chronic exposure to stress leads to adverse health outcomes for our wound patients and ourselves. Stress initially causes a release of catecholamines followed by cortisol. The steroid cortisol functions as we know steroids do, dampening the immune system and delaying healing. Short-term exposure to cortisol can be beneficial, acting as an anti-inflammatory agent and mobilizing glucose to use during a stress response. However, long-term response contributes to inflammation and can increase the experience of pain.⁸ This may be due to cortisol depletion during prolonged or exaggerated stress or due to a mechanism like insulin resistance in diabetes of decreased sensitivity or downregulation of glucocorticoid receptors.⁸ The chronic inflammation secondary to prolonged or exaggerated stress induces oxidative and nitrosative stress, free radical damage, cellular death, aging, and systemic tissue degeneration.9,10 Chronic stress can contribute to the development of atherosclerotic vascular disease through the promotion of hypertension and hyperlipidemia,⁸ immune dysfunction, and psychological issues like sleep deprivation and anxiety.²

Stress and neglect can be experienced so profoundly that they are associated with changes in the expression of DNA, known as epigenetic changes.³ Epigenetic changes are heritable and can be passed down through generations. Adverse childhood events are associated with epigenetic changes, including DNA hypo and hypermethylation and telomere shortening.³ Epigenetic changes have also been implicated in the inflammation associated with type 2 diabetes through histone modifications that potentiate inflammatory macrophage phenotypes.^11,12

The association between stress and wound repair is statistically significant and clinically relevant for wound patients.¹³ For example, patients with higher reported stress levels on the day of biopsy have been shown to have delayed healing.¹³ Psychological stress impacts healing due to a constellation of biological and behavioral factors. Due to our biochemical stress response, chronic wounds experience hypoxia, decreased cytokines, and alterations in matrix metalloproteinases.¹³ Other potential biological etiologies of delayed wound healing related to psychological stress are from alterations in immune response such as decreased neutrophil infiltration and antimicrobial peptides, which leads to increased rates of infection.¹³ The physiologic stress response also alters the microbiome. High levels of oxidative stress, which occurs in many chronic wounds, decrease the diversity of wound microbiota and promote the formation and maturation of biofilm,¹⁴ which is associated with delayed wound healing.

Thankfully, many protective factors offer us mental and physiologic resilience to the toxic stress that can potentiate adverse health outcomes. Stress is unavoidable in life, especially in the last few years. Family and social support are potent protectors against damage from stress and neglect. Meeting the basic needs of food, shelter, and health services and consistent family life where they are cared for and supported are also protective factors.² The community we inhabit can also provide protective factors against the damage from stress. Community structures that protect inhabitants offer access to health care, high-quality pre-school, economic and financial help, school programs, adult work with family-friendly policies, intolerance of violence, and residents feeling connected to each other and involved in their community.² In addition to external protective factors, we can modify what we perceive as stressful and how we respond to it. Therefore, we can decrease the adverse health outcomes associated with stress.⁸

Conclusion

References

1. Medicaid's role in addressing social determinants of health. RWJF. February 1, 2019. Accessed November 11, 2021. https://www.rwjf.org/en/library/research/2019/02/medicaid-s-role-in-addressing-social-determinants-of-health.html
2. Preventing adverse childhood experiences |violence prevention|injury Center|CDC. Centers for Disease Control and Prevention. April 6, 2021. Accessed November 16, 2021. https://www.cdc.gov/violenceprevention/aces/fastfact.html
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14. Kim JH, Ruegger PR, Lebig EG, et al. High Levels of Oxidative Stress Create a Microenvironment That Significantly Decreases the Diversity of the Microbiota in Diabetic Chronic Wounds and Promotes Biofilm Formation. Front Cell Infect Microbiol. 2020;10:259. doi:10.3389/fcimb.2020.00259