Severe gammaherpesvirus-induced pneumonitis and fibrosis in syngeneic bone marrow transplant mice is related to effects of transforming growth factor-ß.

ABSTRACT

Pulmonary infections and pneumonitis occur frequently after hematopoietic stem cell transplantation. Using a syngeneic mouse model of bone marrow transplantation (BMT), we have previously demonstrated that BMT mice are more susceptible to acute gammaherpesvirus 68 (MHV-68) replication at day 7 after infection. By day 21, the virus is latent in lungs of BMT and control mice, and there is no difference in viral load. Despite similar latent viral load, BMT mice develop severe pneumonitis associated with reduced oxygen saturation, fibrosis, peripheral inflammation, hyaline membranes, and foamy alveolar macrophages, a phenotype that persists for 7 weeks after infection. BMT mice demonstrate increased bronchoalveolar lavage (BAL) cells, and this population is enriched in neutrophils and T cells. Alternatively, activated macrophages appear earlier than do classically activated macrophages. BAL fluid from BMT mice at day 21 after infection contains increased levels of hydrogen peroxide, nitrite, and transforming growth factor-ß (TGF-ß). Mice expressing the dominant-negative transgene dn-TGFßRII in multiple cell types were used as BMT donors. BMT mice with T-cell dnTGFßRII are largely protected from the pneumonitis phenotype, whereas mice with CD11c-dnTGFßRII BMT mice are only modestly protected from pneumonitis. Protection in BMT mice with T-cell dnTGFßRII is associated with decreased TGF-ß derived from parenchymal cells in the BAL fluid, lower nitrite levels, and reduced apoptosis, whereas alternatively activated macrophage markers are unchanged.