title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pharmacology, Universidade Federal do Paraná, Curitiba, PR, Brazil.
authors.forename: Evelise Fernandes
authors.initials: EF
authors.lastname: Pietrovski
authors.forename: Kátia Sabrina
authors.initials: KS
authors.lastname: Paludo
authors.forename: Daniel Augusto Gasparin Bueno
authors.initials: DA
authors.lastname: Mendes
authors.forename: Fernando de Souza Fonseca
authors.initials: Fde S
authors.lastname: Guimarães
authors.forename: Silvio Sanchez
authors.initials: SS
authors.lastname: Veiga
authors.forename: Dorly de Freitas
authors.initials: Dde F
authors.lastname: Buchi
authors.forename: Raphael Gomes
authors.initials: RG
authors.lastname: Fonseca
authors.forename: Aleksander Roberto
authors.initials: AR
authors.lastname: Zampronio
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: João Bosco
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
authors.forename: Michel Fleith
authors.initials: MF
authors.lastname: Otuki
authors.forename: Daniela Almeida
authors.initials: DA
authors.lastname: Cabrini
mesh_terms: D000287:Administration, Topical; D000818:Animals; D049109:Cell Proliferation; D004149:Dioxoles / Q000494:pharmacology; D005260:Female; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D011804:Quinolines / Q000494:pharmacology; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D012871:Skin Diseases / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: C487113:2-((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; D004149:Dioxoles; C105311:FR 173657; D018809:Proliferating Cell Nuclear Antigen; D011804:Quinolines; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D013449:Sulfonamides; D013755:Tetradecanoylphorbol Acetate