Expansion of interferon-gamma-producing lung lymphocytes in mouse silicosis

Silicosis is characterized by mononuclear cell inflammation with macrophage activation, accumulation of lymphocytes, and fibrosis. Interferon-gamma (I FN-gamma) is a lymphocyte cytokine with broad effects, particularly macroph age activation. Mice exposed to an aerosol of cristobalite silica (70 m/m(3 ), 12 d, 5 Nd) developed diffuse pulmonary pathologic changes with macropha ge, lymphocyte, and neutrophil recruitment, and increased lung collagen. IF N-gamma messenger RNA (mRNA) was more abundant by semiquantitative reverse transcription-polymerase chain reaction in the lungs of silica-exposed mice than in control animals. IFN-gamma mRNA transcripts were detected by in si tu hybridization with digoxigenin-labeled complementary DNA probes in norma l mouse lung tissue within bronchial-associated lymphoid tissues (BALT). In silica-exposed mice, mononuclear cells with IFN-gamma mRNA were more numer ous in the silicotic lesions and enlarged BALT structures. Lung-cell suspen sions were prepared by enzyme digestion, stained with fluorescent-labeled a ntibodies against intracellular cytokines, and enumerated by flow cytometry . The percentage of cells producing IFN-gamma was increased in silicotic mi ce (19% versus 11%). Interleukin (IL)-4 mRNA transcripts were less abundant in the lung tissue from silica-exposed mice than in control mice. Cells st aining for IL-4 mRNA were found rarely in either the air-sham or the silica -exposed mouse lungs, and almost all appeared to be within BALT structures. Approximately 3% of cells stained for IL-4 in the digested lungs from both groups. Similar cytokine patterns were observed in mediastinal lymph node/ thymus and spleen tissues. The augmented IFN-gamma response, with IL-4 unch anged or decreased, in the lung lesions and lymphoid tissue of mice with si licosis suggests a Th-1-like lymphocyte-mediated immune-inflammatory respon se.