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Bleomycin Lung Injury in Interleukin-12 Knockout Mice* FREE TO VIEW

Richard L. Kradin, MD; Hideo Sakamoto, PhD; Long Hai Zhao, MD; Carol Leary, BA
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*From the Immunopathology Unit of the Massachusetts General Hospital, Boston, MA

Correspondence to: Richard L. Kradin, MD, Director of Pulmonary Immunology and Molecular Biology, Massachusetts General Hospital, 100 Blossom St, Cox 506, Boston, MA 02114

Chest. 2001;120(1_suppl):S10-S11. doi:10.1378/chest.120.1_suppl.S10
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Intratracheal administration of bleomycin produces a pulmonary fibroinflammatory response. Interleukin (IL)-12 promotes the production of T-helper 1 cytokines and antagonizes T-helper 2 pathways. We hypothesized that IL-12 would enhance pulmonary inflammation and ameliorate the fibrosis caused by bleomycin. C57BL/6 mice received 0.075 U of bleomycin or saline solution intratracheally and were killed at intervals between 24 h and 3 weeks. IL-12 expression by blood monocytes and large bronchoalveolar mononuclear cells (BAMC) was examined by ribonuclease protection assay. Pulmonary inflammation and cytokine release were investigated by immunohistochemistry and enzyme-linked immunosorbent assay, respectively; lung fibrosis was determined by histology and hydroxyproline assay. After bleomycin administration, CD11b+ blood monocytes showed a peak in IL-12 production at day 3 that returned toward baseline at day 5. BAMC exhibited a larger peak of IL-12 expression at day 5 that returned rapidly to baseline at day 7. IL-12 production by BAMC correlated with pulmonary lymphocytic inflammation in situ and with interferon-γ production by T lymphocytes. IL-12 production by BAMC was correlated inversely with expression of IL-10, which peaked at day 7 and remained elevated at day 14; blood monocytes did not express IL-10 after bleomycin administration. IL-12 p40 knockout mice showed significantly decreased pulmonary mononuclear cell inflammation at day 7 compared to wild-type control mice. However, pulmonary fibrosis was significantly increased at day 14. We conclude that IL-12 modulates the pulmonary inflammatory and profibrotic response to bleomycin. Early T-helper 1 inflammation mediated by mononuclear cell expression of IL-12 may protect the lung from late fibrosis.

Abbreviations: BAMC = bronchoalveolar mononuclear cell; IL = interleukin




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