This Article Full Text Full Text (PDF) All Versions of this Article: 2007-0299OCv1 38/5/566    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Saito, F. Articles by Ishizaka, A. PubMed PubMed Citation Articles by Saito, F. Articles by Ishizaka, A.

Role of Interleukin-6 in Bleomycin-Induced Lung Inflammatory Changes in Mice

¹ Division of Pulmonary Medicine, and ³ Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo, Japan; and ² Inhalation Toxicology Research Team, National Institute for Environmental Studies, Tsukuba, Japan

Correspondence and requests for reprints should be addressed to Sadatomo Tasaka, M.D., Division of Pulmonary Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: tasaka{at}cpnet.med.keio.ac.jp

Interleukin-6 (IL-6) is known to be involved in the pathogenesis of various inflammatory diseases, but its role in bleomycin (BLM)-induced lung injury and subsequent fibrotic changes remains to be determined. We evaluated the role of IL-6 in the lung inflammatory changes induced by BLM using wild-type (WT) and IL-6–deficient (IL-6^–/–) mice. The mice were treated intratracheally with 1 mg/kg BLM and killed 2, 7, or 21 days later. Lung Inflammation in the acute phase (Days 2 and 7) was assessed by differential cell counts in bronchoalveolar lavage (BAL) fluid and cytokine levels in the lung. Lung fibrotic changes were evaluated on Day 21 by histopathology and collagen assay. On Day 2, BLM administration induced significant increases in the numbers of total cells, macrophages, and neutrophils in BAL fluid, which were attenuated in IL-6^–/– mice (P < 0.05). Lung pathology also showed inflammatory cell accumulation, which was attenuated in the IL-6^–/– mice compared with WT mice. In WT mice, elevated levels of TGF-β₁ and CCL3 were observed 2 and 7 days after BLM challenge, respectively. On Day 7, BLM-induced inflammatory cell accumulation did not differ between the genotypes. Lung pathology 21 days after BLM challenge revealed significant fibrotic changes with increased collagen content, which was attenuated in IL-6^–/– mice. Although the TGF-β₁ level in the lung did not differ between the genotypes on Day 21, CCL3 was significantly lower in IL-6^–/– mice. These results indicate that IL-6 may play an important role in the pathogenesis of BLM-induced lung injury and subsequent fibrotic changes.

Key Words: IL-6 • bleomycin • fibrosis • TGF-β • CCL3

CLINICAL RELEVANCE This study enhances our knowledge of the pathogenesis of lung injury and subsequent fibrotic change. IL-6 plays an important role in the development of bleomycin-induced lung inflammation and fibrosis, possibly through the up-regulation of TGF-β1 and CCL3.