Naftopidil reduced the proliferation of lung fibroblasts and bleomycin-induced lung fibrosis in mice.

Abstract

Naftopidil, an α-1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α-1 adrenoceptor inhibitor. We examined the incorporation of 5-bromo-2'-deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme-linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound-healing assay, and mRNA expressions of type IV collagen and α-smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin-induced lung fibrosis in mice were evaluated using histology, micro-computed tomography, and surfactant protein-D levels in serum. Naftopidil, dose-dependently but independently of phenoxybenzamine, inhibited 5-bromo-2'-deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α-smooth muscle actin in one normal lung fibroblast line. Histological and micro-computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein-D levels in bleomycin-induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis.

• Authors: Hirokazu Urushiyama, Yasuhiro Terasaki, Shinya Nagasaka, Nariaki Kokuho, Youko Endo, Mika Terasaki, Shinobu Kunugi, Kosuke Makita, Hideaki Isago, Keisuke Hosoki, Kunihiko Souma, Takashi Ishii, Hirotaka Matsuzaki, Yoshihisa Hiraishi, Yu Mikami, Satoshi Noguchi, Hiroyuki Tamiya, Akihisa Mitani, Yasuhiro Yamauchi, Akira Shimizu, Takahide Nagase
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 23 Issue 5 Pg. 3563-3571 (05 2019) ISSN: 1582-4934 [Electronic] England
• PMID: 30873733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Adrenergic alpha-Antagonists
• Naphthalenes
• Piperazines
• Pulmonary Surfactant-Associated Protein D
• Bleomycin
• naftopidil

Topics

• Adrenergic alpha-Antagonists (pharmacology)
• Animals
• Bleomycin
• Cell Cycle (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Cells, Cultured
• Fibroblasts (drug effects, metabolism)
• Humans
• Idiopathic Pulmonary Fibrosis (chemically induced, metabolism, prevention & control)
• Lung (drug effects, metabolism, pathology)
• Mice, Inbred C57BL
• Naphthalenes (pharmacology)
• Piperazines (pharmacology)
• Pulmonary Surfactant-Associated Protein D (blood)
• X-Ray Microtomography