Introduction Transforming Growth Factor-beta (TGFβ) promotes anti-proliferative and pro-apoptotic pathways in lung epithelial cells, both of which have been implicated in the pathogenesis of IPF. TGFβ must be activated before it can mediate these events. Acute exacerbations of IPF are characterised by widespread epithelial cell apoptosis. The precise cause of these exacerbations is not known. The Influenza A virus is a single-stranded segmented RNA virus that infects epithelial cells leading to cell death and injury, and can also activate TGFβ. The role of infection in acute exacerbations of IPF is unclear. The aim of this study is to investigate the effect of influenza infection on bleomycin-induced pulmonary fibrosis and TGFβ activation in vivo.
Materials and Methods 60 U of bleomycin was instilled into the lungs of 6–8 week old male C57Bl/6 mice. After 28 days mice were exposed intranasally with 10, 20 Units of influenza virus ‘x31’ or PBS, and the lungs harvested 5 days later. Bronchoalveolar lavage (BAL) was performed and lung tissue harvested for mRNA analysis, histology and hydroxyproline levels. All animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals.
Results Mice exposed to bleomycin and infected with influenza lost less weight compared with saline-exposed influenza-infected animals. However, the lungs from bleomycin-exposed, influenza-infected mice showed increased lung damage with more matrix deposition on trichrome staining than saline-exposed, influenza-infected mice. Saline-exposed, influenza-infected mice demonstrated the anticipated dose dependent increase in BAL lymphocytosis as well as apoptosis staining in histological TUNEL assessment. However, in bleomycin-exposed mice, influenza infection did not promote enhanced BAL lymphocytosis or apoptosis. However, influenza appeared to enhance the fibrotic response demonstrated by an increase in matrix deposition on masson’s trichrome and increased lung hydroxyproline levels in influenza infected bleomycin exposed mice, as early as 5 days post infection.
Conclusions These data suggest that influenza infection may exacerbate lung fibrosis by promoting epithelial apoptosis.
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