Sociogenomic Approach to Wound Care: A New Patient-Centered Paradigm

Abstract

Psychoneuroendocrinology studies provided first insight into social determinants of wound healing. Social stressors impede wound healing. In 2005, we first reported that the transcriptome of wound-site neutrophil is highly responsive to psychological stress in young men. Bioinformatics processing of transcriptome-wide data from neutrophils provided first insight into social transduction pathways relevant to wound healing. In 2010, Idaghdour et al. presented striking evidence demonstrating that genetic factors are responsible for only 5% of the variation in genomic expression. In contrast, the living environment of the individual, urban or rural, was responsible for as much as 50% of such variation. Genetic and environmental factors acted in a largely additive manner. This observation may be credited as the foundation stone of human social genomics. The environment of a patient, including social factors, influences gene expression relevant to wound healing. The nonhealing wound itself and its worsening outcome, including pain, are likely to cause stress. Conversely, positive social interactions may circumvent barriers to wound healing. Thus, interventions directed at the social environment of a wound care patient are likely to help manage wound chronicity. The genomic and related Big Data technology platforms have vastly improved during the past 5 years during which these technologies have also become widely accessible and affordable. Thus, this is the right time to revisit the choice of technologies for the study of social genomics of wound healing. Against the backdrop of our current understanding of the mechanisms of wound healing, such precision approach is likely to transform wound care and its outcomes making it patient-centered and, therefore, more effective.

Thirteen women psychologically stressed because of caring for demented relatives were experimentally wounded to obtain first insight from a well-controlled study demonstrating that caregiver stress impedes wound healing.¹ Peripheral-blood leukocytes were impaired in their ability to mount a response that induces the interleukin-1β gene in response to lipopolysaccharide stimulation compared with cells from those who were not subject to caregiver stress. Not just inducible interleukin-1β gene alone, follow-up studies in our laboratory demonstrated that in psychologically stressed young men, of the 22,283 transcripts surveyed in wound-site neutrophils, 328 genes were downregulated and 264 genes were upregulated in all subjects studied.² Functional analyses of the transcriptome data revealed that stress tilted the balance of the transcriptome toward genes encoding proteins responsible for cell cycle arrest, death, and inflammation. The observation that psychosocial stress impairs wound healing have robust support from a number of independent experimental settings, including hostile marital interactions,³ examination stress,² wound-related pain,⁴ anger,⁵ and social isolation.⁶ Wound can be painful. Anxiety and depression can make pain worse. Pain can slow healing. Furthermore, psychological stress can adversely influence healing outcomes by promoting the adoption of health-damaging behaviors.⁷ For example, self-cutting behavior is common among inmates.⁸ The influence of social factors on wound healing has a broad base. Worse clinical and functional outcomes for minority children compared with white children have been reported for injury in children. In such cases, African American race is recognized as an independent predictor of mortality. These disparities persist even when injury severity and socioeconomic status are controlled in the experiment design.⁹ Consistently, in adults, socioeconomic factors, including poorer household income, are strongly associated with an increased risk of postoperative surgical site infections after lower extremity revascularization.¹⁰ The study of healing rates in a 27 year data set of natural injuries and illnesses in wild baboon males concluded that social status predicts wound healing. Alpha male baboons, with high glucocorticoids and highest testosterone and reproductive effort, healed significantly faster than other males.¹¹ The case for social factors influencing healing outcomes is compelling. The stage is thus set for looking at environmental modulation, including social influence, on gene expression relevant to wound healing.

The environment of a patient, including social factors, influences gene expression relevant to wound healing. Such altered expression of gene manifest function that, on the one hand, may directly influence the trajectory of wound healing. On the other hand, such altered expression of genes in different tissue compartment of the body may directly or indirectly change the social response of the person to the environment, thus indirectly influencing pathways relevant to wound healing. The nonhealing wound itself and its worsening outcome, including pain, are likely to cause stress. Other relevant factors such as social isolation, mood disorders, demoralization, community stress, reduced independence, limited ability to perform activities of daily living, low self-esteem, and poor body image are likely to drive genomic changes impeding wound healing through social signal transduction.^12,13 Conversely, positive social interactions circumvent barriers to wound healing. Positive social interactions influence the activity of the hypothalamic-pituitary-adrenal (HPA) axis to restore wound healing. Positive social interactions is known to antagonize the effects of stress on wound healing through a mechanism that involves oxytocin-induced suppression of the HPA axis.¹⁴ Thus, interventions directed at the social environment of a wound care patient are likely to help manage wound chronicity. Such interventions are likely to impact gene expression via epigenetic pathways. These pathways produce heritable changes in gene expression that do not involve any change in the sequence of DNA. DNA methylation and histone modifications represent two major mechanisms that have profound effects on controlling gene expression. Promoter methylation of noncoding genes contributes to diabetic vasculopathy.¹⁵ Small noncoding genes, miRNA, themselves are also epigenetic modulators of gene expression. In 2007, the first study addressing the significance of miRNAs in wound healing was published.¹⁶ During the course of past decade considerable studies from our as well as other laboratories underscore the significance of miRNAs on wound healing outcomes.^17,18 Early life stress, such as childhood abuse and neglect, can cause epigenomic changes, which in turn may be responsible for development of psychiatric and behavioral disorders later in adult life.¹⁹ When pregnant with the mother, smoking by grandmother increased disease risk in the grandchild independent of the mother's smoking status.²⁰ Thus, in wound care, sociogenomic factors may impact wound healing outcomes across generations.

Infection is a major complicating factor in wound care. More than one-half of all diabetic ulcers are clinically infected.²¹ Considering that standard clinical tests are not likely to detect biofilm infection in all of its forms, that fraction is an underestimation. Infection of the foot is known to precede 80% of nontraumatic lower limb amputations.^22,23 Psychosocial stress suppresses the immune system, thus compromising the body's ability to fight infection.²⁴ How such interaction influences wound infection status, biofilm aggregation, and host-microbial interaction remains to be understood. The Center for Disease Control estimates that 65% of all human infections are caused by bacteria with a biofilm phenotype and National Institutes of Health estimates that this number is closer to 80%. Biofilm infection contributes to chronicity of inflammation and so does stress.^25–27 In turn, inflammation is a risk factor for the development of depressed mood and other neuropsychiatric, neurodevelopmental, and neurodegenerative disorders.²⁸ Biofilm infection impairs granulation tissue collagen causing compromised wound tissue biomechanics making the wound more susceptible to recurrence.²⁹ Biofilm infection impairs the ability of the repaired skin to restore its barrier function.³⁰ Impaired barrier function of the skin is also a hallmark of the aged and diabetic human skin.³¹ Thus, at the intersect of aging and wound infection is a vicious interactive process where stress-induced immune suppression and subdued ability to fight infection is likely to compromise skin function such that the risk of wound recurrence is higher in an already vulnerable aged and/or diabetic skin. The older, evolutionarily conserved defense strategy, innate immunity is of extraordinary significance in this context. Macrophage function is highly responsive to social stress as well as is to wound and infection making it a pointed target of study in the context of the social genomics of the wound.^32–35

In 2010, Idaghdour et al. presented striking evidence demonstrating that genetic factors are responsible for only 5% of the variation in genomic expression. In contrast, the living environment of the individual, urban or rural, was responsible for as much as 50% of such variation.³⁶ The study, and other related evidence, presents a compelling case supporting inclusion of genomic data as an integral component of large social and behavioral data sets. The Health and Retirement Study and the National Longitudinal Study of Adolescent to Adult Health are examples that have shown us the way and its value.^37,38 Social signal transduction is controlled by different and interacting molecular circuits that culminate in gene expression that is different in different subsets of any cell population studied. Thus, in addition to global epigenetic changes, as discussed, one may expect changes in gene expression that are specific to cellular subsets. High-throughput single-cell transcriptomics, not yet commonly applied to social genomics, is a technology platform with considerable potential. Thousands of cells can be profiled simultaneously and analyzed accurately, revealing unique insights into developmental progressions, transcriptional pathways, and the molecular heterogeneity of tissues.³⁹ An average trait within a population is often not representative of the state of any individual cell. Even within populations that are homogeneous in terms of cell surface markers, hidden cell-to-cell variations have direct and significant consequences on system function.⁴⁰

What may be viewed as a subset of the established field of behavioral genetics, social genomics, or sociogenomics is inherently inductive as opposed to deductive by approach. To that end, long-term longitudinal studies in established cohorts of chronic wound patients are likely to provide key insight necessary to develop this emergent field. In contrast, hypotheses based on current literature may be tested in early observational studies on patients with wounds. Sets of data from both of these line of inquiries originating from independent studies will lay the foundation to an effort that has much to give in improving our current paradigm of wound care.

Abbreviations and Acronyms

HPA

hypothalamic-pituitary-adrenal

Author Disclosure and Ghostwriting

No competing financial interests exist.

About the Authors

Professor Chandan Sen is the Editor of Advances in Wound Care.