Murine hypersensitivity pneumonitis: bidirectional role of interferon‐gamma

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Abstract
Summary: C57BL/6 mice were instilled intranasally with optimal doses [150 μg of antigen 3 days a week) of the actinomycete Faeni rectivirgula to induce an experimental hypersensitivity pneumonitis. Some control mice received normal rat IgG as controls, whereas other mice received 1 mg weekly of rat anti‐murine interferon gamma (IFN‐γ) antibody by the intraperitoneal route and 200 μg by the intranasal route given 2 days before and during the challenge period before each instillation. Control mice developed a clear hypersensitivity pneumonitis characterized by an early neutrophilic response at 3 days and a later influx of mononuclear cells (nine‐ to tenfold increase in cell number. P < 0.001 vs saline instilled mice at 4 weeks post‐treatment). F. rectivirgula instillation determined a sharp increase in the lung index (80% increase in lung weight, P < 0.005 vs saline treated mice), as well as a significant fibrosis at 4 weeks (twofold increase in lung hydroxyproline levels). Cytokine measurements showed that tumour necrosis factor alpha (TNFα) was present in the broncho‐alveolar lavage (BAL) of challenged mice at 4 weeks when the BAL was obtained 8 hr after the last challenge (130 U/ml). Treatment of mice with the monoclonal antibody against IFN‐γ was associated with very few changes in the number of cells in the BAL of challenged mice. The lung index of challenged mice was significantly reduced by infusion of the anti‐IFN‐γ antibody. Anti‐IFN‐γ treatment resulted in decreased levels of TNFα in the BAL of F. rectivirgula after 4 weeks of treatment (56 U/ml, P < 0.01). Moreover, depletion of endogenous IFN‐γ in F. rectivirgula‐instilled mice resulted in a diminished lung fibrotic response (P < 0.01 vs mice treated with F. rectivirgula and control antibody).We also studied the effect of exogenous IFN‐γ administration on the development of lung disease. Groups of mice received recombinant gamma interferon (IFN‐γ) (1000 U) intraperitoneally just before the first treatment and also daily, whereas controls received saline or IFN‐γ alone (no F. rectivirgula challenge). After 4 weeks of treatment, mice were killed and various markers of the disease were evaluated. As mentioned before, bronchoalveolar lavage (BAL) cell number was increased tenfold in mice treated with F. rectivirgula, whereas mice given F. rectivirgula and IFN‐γ had only a threefold increase in BAL cell number, determined mostly by a decrease in alveolar macrophage recruitment in the lungs. The BAL of mice treated with F. rectivirgula alone contained 72 U/ml of tumour necrosis factor alpha (TNFα) and 42 U/ml of interleukin‐1 (IL‐1) after 4 weeks of instillation, whereas BAL from mice given F. rectivirgula and 103 U of IFN‐γ had 18 U/ml of TNFα and 22 U/ml of IL‐1 (both P < 0.01 vs F. rectivirgula‐only treated mice). Infusion of 103 U of IFN‐γ daily significantly reduced lung fibrosis in F. rectivirgula‐instilled mice (a c. 50% reduction in hydroxyproline levels: P < 0.01). Overall, these results suggest that IFN‐γ has a bidirectional role in the development of mouse HP, with a potential for pro‐inflammatory or anti‐inflammatory properties, maybe depending on the quantity generated.