Pulmonary fibrosis in Fra-2 transgenic mice is associated with decreased numbers of alveolar macrophages and increased susceptibility to pneumococcal pneumonia

Am J Physiol Lung Cell Mol Physiol. 2021 May 1;320(5):L916-L925. doi: 10.1152/ajplung.00505.2020. Epub 2021 Mar 3.


Idiopathic pulmonary fibrosis (IPF) is a deadly condition characterized by progressive respiratory dysfunction. Exacerbations due to airway infections are believed to promote disease progression, and presence of Streptococcus in the lung microbiome has been associated with the progression of IPF and mortality. The aim of this study was to analyze the effect of lung fibrosis on susceptibility to pneumococcal pneumonia and bacteremia. The effects of subclinical (low dose) infection with Streptococcus pneumoniae were studied in a well characterized fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of spontaneous, progressive pulmonary fibrosis. Forty-eight hours after transnasal infection with S. pneumoniae, bacterial load was assessed in lung tissue, bronchoalveolar lavage (BAL), blood, and spleen. Leukocyte subsets and cytokine levels were analyzed in BAL and blood. Lung compliance and arterial blood gases were assessed. In contrast to wildtype mice, low dose lung infection with S. pneumoniae in Fra-2 TG mice resulted in substantial pneumonia including weight loss, increased lung bacterial load, and bacteremia. BAL alveolar macrophages were reduced in Fra-2 TG mice compared to the corresponding WT mice. Proinflammatory cytokines and chemokines (IL-1β, IL-6, TNF-α, and CXCL1) were elevated upon infection in BAL supernatant and plasma of Fra-2 TG mice. Lung compliance was decreased in Fra-2 TG mice following low dose infection with S. pneumoniae. Pulmonary fibrosis increases susceptibility to pneumococcal pneumonia and bacteremia possibly via impaired alveolar bacterial clearance.

Keywords: Streptococcus pneumoniae; bacteremia; idiopathic pulmonary fibrosis; lung fibrosis; pneumonia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Disease Susceptibility
  • Fos-Related Antigen-2* / genetics
  • Fos-Related Antigen-2* / metabolism
  • Macrophages, Alveolar* / metabolism
  • Macrophages, Alveolar* / microbiology
  • Macrophages, Alveolar* / pathology
  • Mice
  • Mice, Transgenic
  • Pneumonia, Pneumococcal* / genetics
  • Pneumonia, Pneumococcal* / metabolism
  • Pneumonia, Pneumococcal* / microbiology
  • Pneumonia, Pneumococcal* / pathology
  • Pulmonary Fibrosis* / genetics
  • Pulmonary Fibrosis* / metabolism
  • Pulmonary Fibrosis* / microbiology
  • Pulmonary Fibrosis* / pathology
  • Streptococcus pneumoniae / metabolism*


  • Cytokines
  • Fos-Related Antigen-2
  • Fosl2 protein, mouse