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Modulation
of Inflammation by Stress and Psychosocial Factors
Dr. Phillip Marucha
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Stress causes
a release of hormones, including glucocorticoids which reduce the
production of cytokines, e.g., IL-1, and alter leukocyte trafficking
and thus, stress is immunosuppressive. Wound healing is orchestrated
by inflammation, making it an excellent model for investigating
the interaction between stress and psychosocial factors. In fact,
our previous studies have demonstrated that stress was associated
wit a 25-40% delay in wound closure across the models tested. How
stressors are perceived and individual differences in responsiveness
to a perceived stressor can be more important than objective features
of the stressor. Thus, an individual's beliefs, attitudes, and values
will alter their response to a stressor. For example, socially isolated
individuals, in contrast to embedded, tend to show a stronger, protracted
stress response. Preliminary studies have demonstrated that individuals
that score high in loneliness and dysphoria are slower to heal standardized
wounds. The focus of this proposal is to understand the mechanisms
by which psychosocial factors impact on inflammatory processes required
for healing. Our working hypotheses; psychological distress delays
wound healing and this is the result of dysregulating neuroendocrine
pathways, particularly glucocorticoids, that inhibit inflammatory
responses critical to the early phases of wound healing. Psychological
distress is a function of exposure to stressors and of personality
attributes that affect the appraisal of events as stressors and
psychosocial that augment/buffer the perceived consequences of the
stressor. In order to truly understand the mechanisms for stress
and psychosocial factors effects on wound healing, we must go directly
to the wound sites. Since oral wounds are amenable to multiple woundings
without significant scarring, we can use our human model to investigate
altered responses at the wound sites.
The basic model that will be used involves recruiting 75 subjects
from the following four groups: individuals that score high or low
for loneliness and high and low for dysphoria, for a total of 300
subjects. Each individual will have two 2.0 mm. wounds placed, one
on each side of the palate. They will then be chosen for biopsy,
at random, at 1, 3, or 5 days after wounding in order to determine
the affect of stress and personality attributes on inflammatory
processes within the healing wound. Biopsied tissue will be analyzed
for effects on cellularity of the wound, pro-inflammatory cytokine/chemokine,
and growth factor gene expression, and pro-inflammatory cytokine/chemokine
protein expression. The impact of naturalistic stressors, and HPA
reactivity to an acute stressor will be used to determine how personality
attributes and stress influence tissue an neuroendocrine responses
that are responsible for altering early healing. Cytokine production,
chemotaxis and the expression of adhesion molecules will be measured
in peripheral blood cells to determine whether altered recruitment
and activation occurring in tissue samples is a result of altered
peripheral blood responses, altered tissue responsiveness, or both.
The alteration in the kinetic pattern of the inflammatory response
is critical knowledge for the development of the most appropriate
and efficient intervention. If stress affects all parameters through
the wounding process, then an intervention might be required that
is sustained throughout healing. Alternatively, if stress only affects
one critical stage of the response, e.g., the recruitment of macrophages
to the wound site, then the intervention, whether psychological
or biological, may be specifically targeted to that time and that
process. This model will make it possible to understand these interactions,
and as a result, psychological.biological parameters can identify
individuals at risk and appropriate interventions can be developed.
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