Respiratory Reovirus 1/L Induction of Intraluminal Fibrosis a Model of Bronchiolitis Obliterans Organizing Pneumonia Is Dependent on T Lymphocytes

摘要

Bronchiolitis obliterans organizing pneumonia (BOOP) is a clinical syndrome characterized by perivascular/peribronchiolar leukocyte infiltration leading to the development of intraalveolar fibrosis. We have developed an animal model of BOOP where CBA/J mice infected with 1 × 10⁶ plaque-forming units (PFU) reovirus 1/L develop follicular bronchiolitis and intraalveolar fibrosis similar to human BOOP. In this report, we demonstrate a role for T cells in the development of intraluminal fibrosis associated with BOOP. Corticosteroid treatment of reovirus 1/L-infected mice both inhibited the development of fibrotic lesions when administered early in the time-course and promoted the resolution of fibrotic lesions when corticosteroid administration was delayed. Further, the depletion of either CD4⁺ or CD8⁺ T cells before reovirus 1/L infection also inhibited fibrotic lesion development. Both corticosteroid treatment and depletion of CD4⁺ or CD8⁺ T cells also resulted in decreased expression of the proinflammatory and profibrotic cytokines, interferon (IFN)-γ and monocyte chemoattractant protein-1 (MCP-1). Further, treatment of mice with a neutralizing monoclonal antibody to IFN-γ also significantly inhibited the development of fibrosis. Taken together, these results suggest a significant role for T cells in the development of reovirus 1/L-induced BOOP fibrotic lesions in CBA/J mice and suggests that TH1-derived cytokines, especially IFN-γ, may play a key role in fibrotic lesion development.