Heterogeneous pathological outcomes after experimental pH1N1 influenza infection in ferrets correlate with viral replication and host immune responses in the lung

Vidaña, Beatriz; Martínez, Jorge; Martínez-Orellana, Pamela; García Migura, Lourdes; Montoya, María; Martorell, Jaime; Majó, Natàlia

Yang et al. [63] have recently demonstrated that pH1N1 can induce caspase-3-dependent apoptosis in alveolar epithelial cells (AEC). In our study, the animals with severe lung lesions presented with increased inductions of both the BAX and CASP8 pro-apoptotic genes in the lungs. However, immunohistopathological analyses revealed that apoptotic cells at 4 and 7 dpi were mainly identified as macrophages and neutrophils. This finding may elucidate another mechanism of lung tissue damage that is mediated by a delayed clearance of inflammatory cells from infected lungs. The occurrence of complete resolution of inflammation requires apoptotic neutrophils to be cleared by local tissue macrophages. However, if either neutrophil apoptosis or the clearance of apoptotic neutrophils by macrophages is delayed, inflammation-related tissue damage occurs and leads to the exacerbation of inflammation [64, 65] due to increased numbers of inflammatory cells in apoptosis and increased gene expression of BAX and CASP8 that were observed in the ferrets with severe lung lesions. Moreover, these findings are likely related to the delayed viral clearance and the positive feedback loop of proinflammatory cytokines.