A murine model of airway fibrosis induced by repeated naphthalene exposure.
The airway epithelium serves as a biological barrier essential for host defense against inhaled pollutants. While chronic epithelial injury, commonly associated with chronic obstructive pulmonary disease and bronchiolitis obliterans syndrome, often results in airway fibrosis, limited animal models of airway fibrosis have been established. Club cells (Clara cells) in the small airways represent an important population of epithelial progenitor cells and also the principal site of localization of the cytochrome P-450 monooxygenase system, which metabolically activates xenobiotic chemicals such as naphthalene by converting them to toxic epoxide intermediates. We hypothesized that repeated exposure to naphthalene may cause prolonged loss of club cells, triggering aberrant local epithelial repair mechanisms that lead to peribronchial fibrosis. We administered intraperitoneal injections of naphthalene to C57/BL6J mice once a week for 14 consecutive weeks. Repeated club cell injury caused by naphthalene triggered regional hyperproliferation of epithelial progenitor cells, while other regions remained denuded or squamated, resulting in fibroblast proliferation and peribronchial collagen deposition associated with upregulation of the fibrogenic cytokines transforming growth factor-β and connective tissue growth factor. The total collagen content of the lung assessed by measurement of the hydroxyproline content was also increased after repeated exposure to naphthalene. These results lend support to the relevance of repeated injury of airway epithelial cells as a trigger for resting fibroblast proliferation and airway fibrosis. This model of airway fibrosis is simple and easy to reproduce, and may be expected to advance our understanding of the pathogenesis and potential treatment of airway fibrotic disorders.
Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Japan. Electronic address: kaoshiba@tokyo-med.ac.jp.
Kazutetsu
K
Aoshiba
Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Japan.
Takao
T
Tsuji
Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Japan.
Masayuki
M
Itoh
Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Japan.
Seitaro
S
Semba
Comprehensive and Internal Medicine, Tokyo Women's Medical University Medical Center East, Japan.
Kazuhiro
K
Yamaguchi
Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Japan.
Hiroyuki
H
Nakamura
Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Japan.
Hidehiro
H
Watanabe
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology
D004785:Environmental Pollutants; D009281:Naphthalenes; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; C031721:naphthalene
Airway fibrosis; COPD; Clara cell; Fibroblast; Naphthalene