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Mechanisms
of Behavioral and Neuroendocrine Regulation of Wound Healing
Dr. John Sheridan |
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We now have
substantial published and preliminary data using a mouse model of
wound healing that parallels the observations obtained from our
multiple human subjects studies on tissue repair. The data reveal
that stress-induced activation of the HPA axis modulates the healing
process both directly and indirectly. Steroid hormones produced
by the HPA axis have been shown to have a direct impact on cytokine
and chemokine gene expression, which in turn indirectly affects
cellular recruitment to the wound site. The use of an animal model
will allow us to delve deeper into the mechanisms that underlie
wound repair. For example, this model will be exploited to examine
the interaction among the CNS, endocrine and immune systems that
contribute to the delay in healing and also decipher the mechanisms
by which the pro-inflammatory process contributes to wound repair.
The overarching hypothesis for this project is that stress-induced
elevation of serum glucocorticoids suppresses chemokine and pro-inflammatory
cytokine production by down-regulating transcription of these genes
at the wound site. Alpha-chemokines, such as IL-8, are important
for recruitment and activation of neutrophils which are the first
recruited cell to the site of tissue damage. Beta-chemokines, including
MCP-1 and MIP-1a, are important for trafficking of macrophages that
quickly follow the neutrophils into the wound area. The recruited
macrophage is a central figure in repair as it is the major source
of pro-inflammatory cytokines and growth factors that orchestrate
the healing process from the deposition of a provisional matrix
to the contracture of myofibroblasts to the formation of scar tissue
(i.e., closed or healed wound). Our data show that both chemokine
and pro-inflammatory cytokine genes are negatively regulated by
glucocorticoids.
The long-term goal is to understand the mechanisms underlying stress-related
changes among the neuroendocrine, chemotactic and inflammatory cytokine
systems which are responsible for altered wound healing in stressed
animals.The data obtained with human subjects thus far are consistent
with the findings with mice, and encourage us to believe that our
approach to this goal is relevant to humans.Therefore, these investigators
will study the kinetics of chemokine and proinflammatory cytokine
responses at the wound site.They will detail the influence of behavior
on the pattern of expression of alpha and beta chemokines as well
as specific pro-inflammatory cytokines involved in the healing surgically-induced
epithelial wounds in SKH-1 female mice. Among the questions
asked by this group are: does behavior-induced HPA activation affect
chemokine gene expression? Does the diminished PMN and monocytic
infiltrate result in decreased production of proinflammatory cytokine
gene expression? What are the relationships among the proinflammatory
cytokines, chemokines and growth factors that contribute to wound
healing?
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