B1 and B2 kinin receptor participation in hyperproliferative and inflammatory skin processes in mice.

Abstract

BACKGROUND:

Kinins are released during dermal injury and inflammation and seem to contribute to the pathogenesis of cutaneous diseases.

OBJECTIVE:

Participation of kinins in skin inflammatory process was evaluated using knockout mice and non-peptide kinin receptor antagonists.

METHODS:

Chronic skin inflammation was induced by multiple applications of TPA in mice ear.

RESULTS:

The B(2) knockout mice (B(2)(-/-)) showed a significant increase of ear weight (23 ± 10%) and epidermal cellular hyperproliferation and acanthosis formation upon histological analysis when compared with wildtype mice. Also, evaluation of PCNA levels by Western blot and immunohistochemistry confirmed the increase in the epidermis hyperproliferation in the ear skin of B(2)(-/-) mice. In contrast, no modification in these parameters was detected in B(1) knockout mice (B(1)(-/-)). However, mice lacking both kinin receptors (B(1)B(2)(-/-)) presented a considerable reduction of epidermis thickness and in PCNA levels. Following the establishment of skin inflammation (5th day of TPA application) treatment with the non-peptide antagonists SSR 240612 (B(1) receptor antagonist), FR 173657 (B(2) receptor antagonist), or SSR 240612 plus FR 173657 topically applied, caused a significant inhibition of ear weight (20 ± 5%, 34 ± 4% and 32 ± 6%, respectively). In the histological analysis, the antagonists produced a reduction in epidermal hyperplasia and acanthosis formation; but the treatment with a combination of the two antagonists did not increase efficacy.

CONCLUSION:

Kinin receptors seem to be involved in the control of the keratinocyte hyperproliferative process, and non-peptide kinin receptor antagonists may be useful tools in the treatment of hyperproliferative skin disorders.

• Authors: Evelise Fernandes Pietrovski, Kátia Sabrina Paludo, Daniel Augusto Gasparin Bueno Mendes, Fernando de Souza Fonseca Guimarães, Silvio Sanchez Veiga, Dorly de Freitas Buchi, Raphael Gomes Fonseca, Aleksander Roberto Zampronio, Michael Bader, João Bosco Pesquero, Juliano Ferreira, Michel Fleith Otuki, Daniela Almeida Cabrini
• Journal: Journal of dermatological science (J Dermatol Sci) Vol. 64 Issue 1 Pg. 23-30 (Oct 2011) ISSN: 1873-569X [Electronic] Netherlands
• PMID: 21840178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide
• Dioxoles
• FR 173657
• Proliferating Cell Nuclear Antigen
• Quinolines
• Receptor, Bradykinin B1
• Receptor, Bradykinin B2
• Sulfonamides
• Tetradecanoylphorbol Acetate

Topics

• Administration, Topical
• Animals
• Cell Proliferation
• Dioxoles (pharmacology)
• Female
• Inflammation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Proliferating Cell Nuclear Antigen (biosynthesis)
• Quinolines (pharmacology)
• Receptor, Bradykinin B1 (metabolism)
• Receptor, Bradykinin B2 (metabolism)
• Skin Diseases (pathology)
• Sulfonamides (pharmacology)
• Tetradecanoylphorbol Acetate (pharmacology)