B-1 and B-2 kinin receptor participation in hyperproliferative and inflammatory skin processes in mice

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 (B1B2-/-) 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. (C) 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Univ Fed Parana, Ctr Politecn, Setor Ciencias Biol, Dept Farmacol, BR-81530900 Curitiba, Parana, BrazilUniv Fed Parana, Dept Cellular Biol, BR-81530900 Curitiba, Parana, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilMax Delbruck Ctr Mol Med MDC, Berlin, GermanyUniv Fed Santa Maria, Dept Chem, BR-97119900 Santa Maria, RS, BrazilUniv Estadual Ponta Grossa, Dept Pharmaceut Sci, Ponta Grosso, PR, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilWeb of Scienc