Specific induction of oxidative stress in terminal bronchiolar Clara cells during dimethylarsenic-induced lung tumor promoting process in mice

An, Yan; Kato, Koichi; Nakano, Masayuki; Otsu, Hiroshi; Okada, Shoji; Yamanaka, Kenzo

doi:10.1016/j.canlet.2004.12.029

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Volume 230, Issue 1 , Pages 57-64, 8 December 2005

Specific induction of oxidative stress in terminal bronchiolar Clara cells during dimethylarsenic-induced lung tumor promoting process in mice

Yan An
- Department of Biochemical Toxicology, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
Koichi Kato
- Department of Biochemical Toxicology, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
Masayuki Nakano
- National Hospital Organization Chiba Medical Center, 4-1-2 Tsubakimori, Chuo-ku, Chiba 260-8606, Japan
Hiroshi Otsu
- National Hospital Organization Chiba Medical Center, 4-1-2 Tsubakimori, Chuo-ku, Chiba 260-8606, Japan
Shoji Okada
- University of Shizuoka, 2-12-7 Mariko, Shizuoka 421-0103, Japan
Kenzo Yamanaka
- Department of Biochemical Toxicology, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
- Corresponding author. Tel./fax: +81 47 465 6077.

Received 13 December 2004; received in revised form 15 December 2004; accepted 15 December 2004.

Abstract

The induction of oxidative stress in pulmonary cells during the process of lung tumor promotion by dimethylarsinic acid (DMA), a main metabolite of inorganic arsenics in mammals, was examined by immunohistochemical analysis using a specific antibody against 4-hydroxy-2-nonenal (4HNE) adducts, which are major aldehydic metabolites of lipid peroxidation. We demonstrated that 4HNE-modified proteins existed specifically in the secretory granules in terminal bronchiolar Clara cells. Furthermore, the degree of positive staining increased with the duration of DMA administration. Transmission electron microscopy revealed morphological changes in the Clara cells of DMA-treated mice. These results suggest that Clara cells are the major target cell for DMA-induced oxidative stress and that the cells may play an important role in the lung tumor promotion process in mice.

Keywords: Dimethylarsinic acid, Trivalent dimethylated arsenic, Clara cell, 4-Hydroxy-2-nonenal, Oxidative stress, Lung tumor promotion