Lung fibroblasts contribute to release of Serum Amyloid A as potential biomarker of exacerbation of lung fibrosis in mice [scRNA-seq]

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 (IPF) is currently undefined. Using a well described model of S. pneumoniae (Spn) induced exacerbation of lung fibrosis in mice, we found that platelet-derived growth factor receptor A (PDGFRα) 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. Moreover, lung fibroblasts responded to pneumococcal challenge with increased SAA mRNA and protein levels in vitro. SAA levels were significantly elevated in BAL and plasma of mice with Spn-induced exacerbation of AdTGF-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 interstitial lung disease (AE-ILD) but not in patients without exacerbation. We conclude that 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.