Lung fibroblasts contribute to release of serum amyloid A as potential biomarker of exacerbation of lung fibrosis in mice.

BACKGROUND: Fibroblasts are important contributors to collagen deposition in interstitial lung diseases (ILD), but their inflammatory role in acute exacerbation of ILD including idiopathic pulmonary fibrosis is currently undefined. METHODS: Using a well-described model of Streptococcus pneumoniae-induced exacerbation of lung fibrosis in mice, we found that platelet-derived growth factor receptor A-positive lung fibroblasts developed an early inflammatory phenotype upon infection, including increased production of serum amyloid A (SAA) proteins, as determined by RNA sequencing, single-cell RNA sequencing and secretome profiling of sorted lung fibroblasts. RESULTS: Lung fibroblasts responded to pneumococcal challenge with increased SAA mRNA and protein levels in vitro. SAA levels were significantly elevated in bronchoalveolar lavage (BAL) and plasma of mice with S. pneumoniae-induced exacerbation of adenoviral vector delivery of active transforming growth factor-β1- or bleomycin-induced lung fibrosis. Antibiotic therapy caused a significant drop in SAA levels in BAL and plasma of mice with infection-driven fibrosis exacerbation. Finally, levels of SAA protein were dramatically increased in plasma of patients with acute exacerbation of ILD, but not in patients without exacerbation. CONCLUSION: Analysis of plasma levels of SAA protein may aid in the identification of underlying inflammation in patients with ILD who are more likely to deteriorate towards a critical clinical stage during acute exacerbation.