Background
Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) has a poor prognosis and lacks effective therapy. Animal models that mimic AE-IPF can greatly accelerate investigation of its pathogenesis and development of effective therapy. However, there are few reports of animal models of AE-IPF caused by bacteria. Thus, our study aimed to establish a mouse model of bacterium-induced AE-IPF and explore the potential pathogenic mechanism of AE-IPF.
Conclusions
NTHi infection after BLM-induced IPF can cause AE-IPF in a murine model. This novel model can be used to investigate the pathogenesis of AE-IPF and develop new therapies for AE-IPF caused by bacteria. IL-17 is essential for the development of AE-IPF, and it may be a new therapeutic target for bacteria-induced AE-IPF.
Methods
Mice were instilled intranasally with bleomycin (BLM) followed by non-typeable Haemophilus influenzae (NTHi) strain NT127. Murine survival, bacterial load, body weight and pulmonary histopathological changes were evaluated. We analyzed the T cell and inflammatory cell responses in the lungs.
Results
Infection with 107 CFU NT127 triggered AE in mice with PF induced by 30 μg BLM. Compared with BLM-instilled mice, the BLM/NT127-treated mice showed more obvious airway inflammation, lower survival rate, higher inflammatory cell response, and increased proportions and numbers of IL-17+CD4+, IL-17+ γδ T, IL-22+CD4+ and regulatory T (Treg) cells in lungs. γδ T cells were the predominant source of IL-17. IL-17 gene knockout mice with AE-IPF had quicker body weight recovery, milder pulmonary inflammation and fibrosis, stronger IL-22+CD4+T, TGF-β+ γδ T and Treg cell responses, and weaker neutrophil and eosinophil responses than wild-type mice with AE-IPF. Conclusions: NTHi infection after BLM-induced IPF can cause AE-IPF in a murine model. This novel model can be used to investigate the pathogenesis of AE-IPF and develop new therapies for AE-IPF caused by bacteria. IL-17 is essential for the development of AE-IPF, and it may be a new therapeutic target for bacteria-induced AE-IPF.