Doctoral theses
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Identifier |
000378692 |
Title |
Εκλυτική ορμόνη της κορτικοτροπίνης (CRH) και των γλυκοκορτικοειδών στην τραυματική επούλωση |
Alternative Title |
Role of neuropeptide corticotropin releasing (CRH) and glucocorticoids in wound healing |
Author
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Ρασούλη, Όλγα
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Thesis advisor
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Γραβάνης, Αχιλλέας
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Reviewer
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Μαργιωρής, Ανδρέας
Κάραλη, Αικατερίνη
Καστανάς, Ηλίας
Τσατσάνης, Χρήστος
Λιαπάκης, Γεώργιος
Βενυχάκη, Μαρία
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Abstract |
Cutaneous wound healing is a complex process tightly related to inflammation,
which requires the cooperation of several different cell populations and factors.
Corticotropin releasing hormone (CRH) is the main regulator of the hypothalamic‐pituitaryadrenal
(HPA) axis, which mediates the body's response to stress, including inflammation.
The stimulation of CRH by stressful stimuli leads to the release of adrenal glucocorticoids, a
potent endogenous anti‐inflammatory agent. CRH exerts its effects through two main types
of receptor, receptor 1, (CRF1) and receptor 2 (CRF2). The mRNA of CRH and the
immunoreactive peptide and its receptors have been identified in a plethora of peripheral
tissues including the skin. Although it has been shown that peripheral CRH possesses direct
pro‐inflammatory action, its role in the process of cutaneous wound healing remains
unclear.
To study the role of CRH in cutaneous wound healing we used mice with genetic
deletion of CRH (Crh‐/‐). CRH mRNA was detected in both normal and wounded skin of
Crh+/+ mice. Crh‐/ ‐ mice characterized by accelerated wound healing which was
accompanied by rapid progression of inflammation and re‐epithelialization from the second
to the fifth day following the induction of wound compared to wild type mice. Moreover,
Crh‐/‐ mice had higher levels of TGF‐β1 on day 3 when compared with Crh+/+ mice. The
replacement of glucocorticoids on Crh‐/‐ mice accelerated the wound healing even more
during the first day following the induction of wound compared with vehicle alone‐treated
Crh‐/‐ mice and simultaneously accelerated the resolution of the inflammatory response and
increased the number and organization speed of fibroblasts. Finally, administration of
corticosterone restored the tissue levels of TGF‐β1 in Crh‐/‐ mice to those observed in
Crh+/+ mice. Our results suggest that genetic deficiency of CRH is associated with
accelerated wound healing characterized by increased epithelialization and presence of
fibroblasts in the area of the wound in a manner independent of glucocorticoids
insufficiency.
To clarify the role of endogenous CRH in the function of fibroblasts during wound
healing we used primary cultures of fibroblasts derived from neonatal skin of Crh +/+ and
Crh‐/‐ mice. Our studies showed that Crh is expressed in wild type fibroblasts. Moreover,
fibroblasts of both genotypes have functional receptors, as they induce the production of
cAMP. Fibroblasts with genetic deficiency of CRH have higher proliferation and migration
rate and decreased production of IL‐6, TGF‐β1 and collagen in comparison with the
corresponding wild type fibroblasts. The pharmacological blockade of CRF1 using antalarmin
in cultured human fibroblasts led to similar changes on the rate of proliferation an
migration and secretion of IL‐6, with those observed in Crh ‐/‐ fibroblasts. These results
reinforce the importance of CRH in the biology of skin fibroblasts during wound healing.
In summary, our findings from in vivo and in vitro experiments demonstrate for the
first time the important role of locally produced CRH in cutaneous wound healing. The exact
mechanism of action has not been clarified. However it appears that fibroblasts are an
important component in this process.
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Language |
Greek |
Subject |
CRH |
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Corticotropin-Releasing Hormone pharmacology |
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Fibroblasts |
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Glucocorticoids |
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Hypothalamic-pituitary-adrenal axis |
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IL-6 |
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Neurotransmitter Agents pharmacology |
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Skin |
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TGF-β |
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Wound Healing |
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Άξονας υποθάλαμος-υπόφυση-επινεφρίδια |
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Γλυκοκορτικοειδή |
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Δέρμα |
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Επούλωση τραύματος |
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Ινοβλάστες |
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Κορτικοτροπίνης εκλυτική ορμόνη Φαρμακολογία |
Issue date |
2011-12-15 |
Collection
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School/Department--School of Medicine--Department of Medicine--Doctoral theses
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Type of Work--Doctoral theses
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Permanent Link |
https://elocus.lib.uoc.gr//dlib/f/4/2/metadata-dlib-1362732320-93091-14905.tkl
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