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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

Ρασούλη, Όλγα

Thesis advisor

Γραβάνης, Αχιλλέας

Reviewer

Μαργιωρής, Ανδρέας
Κάραλη, Αικατερίνη
Καστανάς, Ηλίας
Τσατσάνης, Χρήστος
Λιαπάκης, Γεώργιος
Βενυχάκη, Μαρία

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.

Language

Greek

Subject

CRH

Corticotropin-Releasing Hormone pharmacology

Fibroblasts

Glucocorticoids

Hypothalamic-pituitary-adrenal axis

IL-6

Neurotransmitter Agents pharmacology

Skin

TGF-β