Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis

PLoS One. 2015 Jan 15;10(1):e0116775. doi: 10.1371/journal.pone.0116775. eCollection 2015.


Background: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a common cause of disease acceleration in IPF and has a major impact on mortality. The role of macrophage activation in AE of IPF has never been addressed before.

Methods: We evaluated BAL cell cytokine profiles and BAL differential cell counts in 71 IPF patients w/wo AE and in 20 healthy volunteers. Twelve patients suffered from AE at initial diagnosis while sixteen patients developed AE in the 24 months of follow-up. The levels of IL-1ra, CCL2, CCL17, CCL18, CCL22, TNF-α, IL-1β, CXCL1 and IL-8 spontaneously produced by BAL-cells were analysed by ELISA.

Results: In patients with AE, the percentage of BAL neutrophils was significantly increased compared to stable patients. We found an increase in the production rate of the pro-inflammatory cytokines CXCL1 and IL-8 combined with an increase in all tested M2 cytokines by BAL-cells. An increase in CCL18 levels and neutrophil counts during AE was observed in BAL cells from patients from whom serial lavages were obtained. Furthermore, high baseline levels of CCL18 production by BAL cells were significantly predictive for the development of future AE.

Conclusions: BAL cell cytokine production levels at acute exacerbation show up-regulation of pro-inflammatory as well as anti-inflammatory/ M2 cytokines. Our data suggest that AE in IPF is not an incidental event but rather driven by cellular mechanisms including M2 macrophage activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Case-Control Studies
  • Chemokine CXCL1 / metabolism
  • Chemokines, CC / metabolism
  • Female
  • Humans
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Interleukins / metabolism
  • Macrophage Activation / physiology*
  • Male
  • Middle Aged
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Tumor Necrosis Factor-alpha / metabolism


  • Chemokine CXCL1
  • Chemokines, CC
  • Interleukins
  • Tumor Necrosis Factor-alpha

Grants and funding

This study was supported by E-RARE project, JRC 2011 IPF-AE (DLR 01GM1210A), (, AP. The article processing charge was funded by the open access publication fund of the Albert Ludwigs University Freiburg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.