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

• Published in: Journal of dermatological science Vol. 64; no. 1; pp. 23 - 30
• Main Authors: Pietrovski, Evelise Fernandes, Paludo, Kátia Sabrina, Mendes, Daniel Augusto Gasparin Bueno, Guimarães, Fernando de Souza Fonseca, Veiga, Silvio Sanchez, Buchi, Dorly de Freitas, Fonseca, Raphael Gomes, Zampronio, Aleksander Roberto, Bader, Michael, Pesquero, João Bosco, Ferreira, Juliano, Otuki, Michel Fleith, Cabrini, Daniela Almeida
• Format: Journal Article
• Language: English
• Published: Netherlands 01.10.2011
• Subjects: Administration, Topical; Animals; Cell Proliferation; Dermatology; 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; Kinin receptor; Kinin receptor knockout mice; SSR 240612; FR 173657; Epidermis hyperproliferation
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/j.jdermsci.2011.06.016

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 B2 knockout mice (B2−/− ) 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 B2−/− mice. In contrast, no modification in these parameters was detected in B1 knockout mice (B1−/− ). However, mice lacking both kinin receptors (B1 B2−/− ) 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 (B1 receptor antagonist), FR 173657 (B2 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.