Suppressive activity of fexofenadine hydrochloride on metalloproteinase production from nasal fibroblasts in vitro.
BACKGROUND
Allergic rhinitis (AR) is an inflammatory disease characterized by nasal wall remodelling with intense infiltration of eosinophils and mast cells/basophils. Matrix metalloproteinases (MMPs), MMP-2 and MMP-9, are the major proteolytic enzymes that induce airway remodelling. These enzymes are also important in the migration of inflammatory cells through basement membrane components.


OBJECTIVE
We evaluated whether fexofenadine hydrochloride (FEX), the carboxylic acid metabolite of terfenadine with selective H(1)-receptor antagonist activity, could inhibit MMP production from nasal fibroblasts (NFs) in response to TNF-alpha stimulation in vitro.


METHODS
NFs were established from nasal polyp-derived fibroblasts (PFs) taken from patients with AR. Nasal mucosal fibroblasts (MFs) were also induced from nasal mucosal tissues from septal deformity patients without allergy. PF and MF (2 x 10(5) cells/mL, each) were stimulated with TNF-alpha in the presence of various concentrations of FEX. After 24 h, culture supernatants were obtained and assayed for MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 levels by ELISA. The influence of FEX on mRNA expression of MMPs and TIMPs in 4 h-cultured cells was also evaluated by real-time RT-PCR. Furthermore, nuclear factor-kappa B (NF-kappa B) activation in fibroblasts treated with FEX for 4 h was examined by ELISA.


RESULTS
FEX at more than 350 ng/mL inhibited the production of MMP-2 and MMP-9 from both PF and MF in response to TNF-alpha stimulation, whereas TIMP-1 and TIMP-2 production was scarcely affected by FEX. FEX also inhibited MMP mRNA expression and NF-kappa B activation in PF and MF after TNF-alpha stimulation.


CONCLUSIONS
The present data suggest that the attenuating effect of FEX on MMP-2 and -9 production from NFs induced by inflammatory stimulation may underlie the therapeutic mode of action of the agent on allergic diseases, including AR.
Asano
K
K
Department of Physiology, School of Medicine, Showa University, Tokyo 142-8555, Japan. asanok@med.showa-u.ac.jp
Kanai
K-I
KI
Suzaki
H
H
D000328:Adult; D002478:Cells, Cultured; D003864:Depression, Chemical; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D045726:Metalloproteases / Q000096:biosynthesis*; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism*; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis
D006634:Histamine H1 Antagonists; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D016593:Terfenadine; C093230:fexofenadine; D045726:Metalloproteases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9