K Asano1, K-I Kanai, H Suzaki. 1. Department of Physiology, School of Medicine, Showa University, Tokyo 142-8555, Japan. asanok@med.showa-u.ac.jp
Abstract
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. CONCLUSION: 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.
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 deformitypatients 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. CONCLUSION: 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.