Role of E-selectin in bleomycin induced lung fibrosis in mice
- Arata Azumaa,
- Satoru Takahashib,
- Masato Nosec,
- Kimi Arakid,
- Masatake Arakie,
- Takuo Takahashia,
- Mayumi Hirosef,
- Hiroto Kawashimaf,
- Masayuki Miyasakaf,
- Shoji Kudoha
- aFourth Department of Internal Medicine, Nippon Medical School, 1–1–5 Sendagi, Bunkyo-ku, Tokyo 113–8602, Japan, bInstitute of Basic Medical Sciences, University of Tsukuba, 1–1–1 Tennoudai, Tsukuba City, Ibaragi 305-8575, Japan, cEhime University School of Medicine, Department of Pathology, Shigenobu-cho, Onsen-gun, Ehime 791–0295, Japan, dInstitute of Molecular Embryology and Genetics and Kumamoto University School of Medicine, 4–24–1 Kuhoriji, Kumamoto City, Kumamoto 862-0976, Japan, eGene Technology Center, Kumamoto University, 2–2–1 Honjo, Kumamoto City, Kumamoto 860-0811, Japan, fOsaka University Medical School, Biomedical Research Center, Department of Bioregulation, 2–2 Yamadaoka, Suita 565–087 1, Japan
- Dr A Azuma
- Received 19 April 1999
- Revision requested 28 June 1999
- Revised 18 October 1999
- Accepted 20 October 1999
Abstract
BACKGROUND Bleomycin (BLM), a well known anti-cancer drug, often causes acute lung injury and fibrosis by mechanisms that are not well understood. It is suspected that some proteases and active oxygen species generated from inflammatory cells cause the lung injury and subsequent lung fibrosis. It was therefore hypothesised that inhibition of adhesion of inflammatory cells to the endothelium might prevent these developments.
METHODS BLM (100 mg/kg) was injected into the tail veins of ICR mice to evaluate the induction of E-selectin, an adhesion molecule known to induce neutrophil attachment on endothelial cells. E-selectin mRNA induction was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The myeloperoxidase (MPO) activities in the lung tissues of BLM treated and control mice were compared to evaluate neutrophil infiltration. Pathological changes in the lungs of soluble E-selectin transgenic mice (TG) and their TG negative (non-TG) littermates after BLM treatment were also compared. Serum samples of TG mice and non-TG mice were tested for their ability to block the binding of sialyl Lewisx to recombinant E-selectin in vitro.
RESULTS E-selectin mRNA was maximally induced at six hours after BLM treatment in the ICR mice. The soluble form of E-selectin which can competitively inhibit the binding of sialylated antigens on inflammatory cells to E- and P-selectins on the endothelium was detected in the serum of TG mice. BLM induced lung fibrosis occurred in non-TG mice but not in TG mice. This result confirms the finding that the serum of TG mice inhibits the binding of sialyl Lewisx to E-selectin in vitro.
CONCLUSION E-selectin plays an essential role in BLM induced lung fibrosis through the induction of neutrophil and other inflammatory cell accumulation, and soluble E-selectin may be of use in the prophylactic treatment of lung fibrosis.
