Experimental and Molecular Pathology 72, 1–9 (2002) doi:10.1006/exmp.2001.2409, available online at http://www.idealibrary.com on IL-12p40 / Mice Treated with Intratracheal Bleomycin Exhibit Decreased Pulmonary Inflammation and Increased Fibrosis Hideo Sakamoto, Long-Hai Zhao, Felipe Jain, and Richard Kradin 1 Immunopathology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114 Received August 13, 2001 Pulmonary lymphohistiocytic inflammation and fibrosis characterize The pathogenesis of murine BLM lung injury has been exten- bleomycin (BLM) lung injury. IL-12, a p70 cytokine produced primar- sively investigated [2, 3]. A role for T-cell-mediated immu- ily by macrophages and dendritic cells, promotes T-helper-1-mediated nity in the pathogenesis of BLM injury has been suggested inflammation. IL-12 production by blood monocytes and bronchoal- based on (1) variations in the susceptibility to BLM lung veolar large mononuclear cells (BAMC) was investigated at Days 1–14 following intratracheal administration of BLM. In the lung, BAMC injury exhibited by certain MHC strains [3], (2) decreased showed a large peak of IL-12 expression at Day 5 that returned rapidly lung injury in nude mice [4], and (3) the beneficial effects toward baseline. IL-12p40 -/- mice treated with BLM intratracheally of eliminating T lymphocytes in vivo via the administration showed less pulmonary mononuclear cell inflammation at Day 7 than of anti-thymocyte globulin [5] or anti-T-lymphocyte mono- wild-type controls, whereas pulmonary fibrosis and hydroxyproline content were increased in IL-12p40 -/- mice at Day 14. The expression clonal antibodies [6, 7]. However, the apparently undimin- of IP-10, RANTES, and eotaxin were decreased in IL-12p40 -/- mice ished development of pulmonary fibrosis in severe combined and lung IL-6 expression was increased, all compared to controls. We immunodeficient (SCID) mice [8] indicates that T lympho- conclude that IL-12 promotes the lymphohistiocytic response to BLM cytes may not be necessary for the development of BLM and may inhibit the late development of pulmonary fibrosis.  2002 Elsevier Science lung injury. Pulmonary mononuclear phagocytes are increased in BLM injury and have been posited to play a central role in patho- genesis [9]. Mononuclear phagocytes exhibit pleiotropic bio- logical activities that include the production of cytokines, toxic free radicals, procoagulants, and fibroblast growth fac- INTRODUCTION tors [10] which can modulate inflammation and fibrosis. IL- 12 is a cytokine produced by macrophages, dendritic cells, and B-lymphocytes [11]. It induces the production of IFN- Bleomycin (BLM) is a mixture of cytotoxic glycopeptides  by lymphocytes [12] and enhances the cytolytic activities isolated from Streptomyces verticillus that produces lung of natural killer cells (NK) [13]. As IL-12 promotes T-helper- parenchymal injury and interstitial fibrosis in humans [1]. 1 (Th1) proinflammatory pathways [14, 15] and inhibits Th2 responses, we hypothesized that IL-12 would promote pulmonary Th1 mononuclear cell inflammation and poten- 1 To whom correspondence should be addressed at Massachusetts General Hospital, Warren 5, Boston, MA 02114. tially inhibit fibrosis in the pulmonary response to BLM. 0014-4800/02 $35.00 1  2002 Elsevier Science All rights reserved.