Macrophage Activation in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Abstract

BackgroundAcute 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.MethodsWe 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.ResultsIn 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.ConclusionsBAL 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.

Mechanisms of Lung Fibrosis Resolution

“…92 The presence of these alternatively activated macrophages has been linked to acute exacerbation of IPF patients consistent with the idea that macrophages can modulate the stability or progression of IPF. 95 When macrophages from the lungs of healthy controls or IPF patients were cultured and stimulated with collagen monomers, the IPFderived macrophages increased expression of profibrotic markers and cytokines, consistent with a classification of the alternative activated state. 96 Although macrophages can clearly promote fibrogenesis, depletion of macrophages during the recovery phase of both toxic liver injury and the lung bleomycin fibrosis models delayed the resolution of fibrosis.…”

Positive fungal quantitative PCR and Th17 cytokine detection in bronchoalveolar lavage fluids: Complementary biomarkers of hypersensitivity pneumonitis?

“…These diseases have in common to lead ultimately to formation of granulomas and a fibrotic phase (Girard et al, 2009;Facco et al, 2011). The mechanisms involved in IPF immunopathology remain poorly understood but include macrophage activation, fibrotic foci formation, possibly Th1 promoted (Schupp et al, 2015;Oruqaj et al, 2015). No Th2 switch was described for any of these ILD.…”

“…A panel of 10 key cytokines/chemokines were selected for testing, based on the scientific literature concerning ILD immunopathology (Mroz et al, 2008;Ye et al, 2009;Joshi et al, 2009;Simonian et al, 2009;Andrews et al, 2016;Tondell et al, 2014;Facco et al, 2011;Schupp et al, 2015;Oruqaj et al, 2015): IL-8, IL-6, TNFα, IFNγ, IL-1β (Th1 response), IL-4 (Th2 response) and IL-17, IL-21 and IL-23 (Th17 response). The TSLP, unexplored up to now, was also measured in patient's BALF (Kuethe et al, 2014).…”

“…IPF is a devastating disease, and its pathogenic mechanisms remain poorly understood (Schupp et al, 2015;Oruqaj et al, 2015).The immunopathology of IPF have only partially been unraveled, showing macrophage activation and fibrotic foci formation, possibly promoted by TNFα and TGFβ (Schupp et al, 2015;Oruqaj et al, 2015). Bronchoalveolar lavage fluids (BALF) samples are often collected for the determination of cell and cytokine profiles, for the biological diagnosis of ILD.…”

Leukocytapheresis for the treatment of acute exacerbation of idiopathic interstitial pneumonias: a pilot study

“…The effectiveness of LCAP is through the removal of activated leukocytes (13). Some investigators have observed activated leukocytes such as neutrophils and macrophages in patients with AE of IIPs (AE-IIPs) (3,14). Therefore, we hypothesized that LCAP may improve the general and respiratory condition of patients with AE-IIPs.…”