Infective exacerbations of chronic inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are associated with incremental scarring and fibrosis and gradual decrements in lung function. Central to this pathology is transforming growth factor-beta (TGFB), a pleiotropic cytokine that regulates cell proliferation, tissue remodelling and lung fibrosis. Our previous studies have demonstrated that TGFB suppresses the immune response, resulting in enhanced viral infection.
Utilising a transgenic mouse model that over-expresses TGFB specifically in the lungs upon doxycycline administration, we have established an acute and chronic model of TGFB expression. In the acute model, TGFB was over-expressed for 2 days prior to influenza A virus (IAV) infection. These mice experienced more severe bronchitis and pneumonia, increased inflammatory cell infiltrates and enhanced cytokine and chemokine production in bronchoalveolar lavage (BAL) fluid compared to mice with normal TGFB levels. These mice also demonstrated a suppressed immune response that was associated with enhanced viral titres.
For the chronic model, TGFB was over-expressed for 8 weeks, which resulted in thickening of the respiratory bronchiole epithelium and surrounding smooth muscle, and an emphysematous appearance within the air spaces, resembling phenotypic changes characteristic of asthma and COPD. Preliminary results in this model demonstrate that IAV infection is more severe compared to mice with normal TGFB levels.
Our transgenic mouse model provides us with a unique tool to evaluate the direct effects of TGFB on viral infection, or in the context of chronic inflammatory lung disease, and to investigate potential therapeutic strategies to combat viral-induced disease exacerbation.