IL ‐17A contributes to HSV 1 infection‐induced acute lung injury in a mouse model of pulmonary fibrosis

Background Patients with idiopathic pulmonary fibrosis ( IPF ) often experience acute exacerbation ( AE ) after an episode of common cold. Aims To establish a mouse model of virus infection‐induced AE ‐ IPF and investigate the mechanism underlying the AE ‐ IPF . Methods Herpes simplex virus 1 ( HSV 1) was inoculated intranasally to wild‐type ( WT ) and IL ‐17A gene knockout ( IL ‐17A ‐/‐ ) mice 21 days after intratracheal administration of bleomycin ( BLM ). Results HSV 1 infection caused acute exacerbation in mice with BLM ‐induced fibrosis. Compared with the BLM +Saline mice, the mice with BLM + HSV 1 showed significantly higher acute lung injury ( ALI ) score ( P  <   0.0001), lower survival rate (100% vs 21.4%, P <  0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid ( BALF ) ( P  =   0.0323), increased proportion of Th17 cells in peripheral blood ( P  =   0.0004) and higher inflammatory factors in BALF . In addition, HSV 1 infection increased the expression of endoplasmic reticulum stress ( ERS )‐related proteins in mice with BLM ‐induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid ( TUDCA , an ERS inhibitor) significantly reduced the IL ‐17A levels in BALF ( P  =   0.0140) and TH 17 cells in the peripheral blood ( P  =   0.0084) of mice with BLM + HSV 1, suggesting that suppression of ERS may reduce TH 17 response in mice with AE ‐ IPF . Compared with WT mice with BLM + HSV 1, IL ‐17A ‐/‐ mice with BLM + HSV 1 had lower ALI score ( P  =   0.0119), higher survival rate (78.6% vs 21.4%, P  =   0.004), improved lung function, and milder inflammatory response. Conclusions HSV 1 infection in addition to BLM ‐induced IPF can successfully establish AE ‐ IPF in mice. IL ‐17A and ERS promote lung inflammation in AE ‐ IPF development.