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Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis.

Schupp JC, Binder H, Jäger B, Cillis G, Zissel G, Müller-Quernheim J, Prasse A - PLoS ONE (2015)

Bottom Line: 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.Furthermore, high baseline levels of CCL18 production by BAL cells were significantly predictive for the development of future AE.

View Article: PubMed Central - PubMed

Affiliation: Department of Pneumology, University Medical Centre, Freiburg, Germany.

ABSTRACT

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.

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Spontaneous macrophage derived chemokine production in IPF patients w/o acute exacerbation.Boxplots of the spontaneous production of A: CCL2, B: CCL17, C: CCL18, D: CCL22, E: IL-1ra, F: TNF-α, G: IL-1β, H: IL-8 and I: CXCL1 protein by BAL cells of patients with IPF. The dark grey boxplots represent patients who suffered from an acute exacerbation (AE, n = 12), the light grey represent patients who did’t suffer from an AE at timepoint of BAL (NoAE, n = 59) (* p<0.05, ** p<0.01, n.s. = not significant).
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pone.0116775.g001: Spontaneous macrophage derived chemokine production in IPF patients w/o acute exacerbation.Boxplots of the spontaneous production of A: CCL2, B: CCL17, C: CCL18, D: CCL22, E: IL-1ra, F: TNF-α, G: IL-1β, H: IL-8 and I: CXCL1 protein by BAL cells of patients with IPF. The dark grey boxplots represent patients who suffered from an acute exacerbation (AE, n = 12), the light grey represent patients who did’t suffer from an AE at timepoint of BAL (NoAE, n = 59) (* p<0.05, ** p<0.01, n.s. = not significant).

Mentions: BAL cells of patients with IPF produced significantly more CCL2, CCL17, CCL18, CCL22, IL-1ra, IL-1β and IL-8 than cells of healthy volunteers (Table 1). There was no difference between IPF patients and controls in TNF-α and CXCL1 production. We compared the spontaneous production of macrophage derived cytokines of the patients with IPF who suffered from an acute exacerbation at time point of BAL against those patients who did not. The twelve patients with acute exacerbation had significantly higher levels of CCL2 (p = 0.002), CCL17 (p = 0.03), CCL18 (p = 0.02), CCL22 (p = 0.009), IL-1ra (p = 0.003), CXCL1 (p = 0.01) and IL-8 (p = 0.02) (Table 1 and Fig. 1). TNF-α and IL-1β were not significantly elevated, although TNF-α showed a trend towards statistical significance. Of the tested chemokines, only CCL2 correlated weakly with baseline FVC % predicted (r = -0.4, p = 0.001) and with baseline CPI (Speamans rho = -0.46, p = 0.003).


Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis.

Schupp JC, Binder H, Jäger B, Cillis G, Zissel G, Müller-Quernheim J, Prasse A - PLoS ONE (2015)

Spontaneous macrophage derived chemokine production in IPF patients w/o acute exacerbation.Boxplots of the spontaneous production of A: CCL2, B: CCL17, C: CCL18, D: CCL22, E: IL-1ra, F: TNF-α, G: IL-1β, H: IL-8 and I: CXCL1 protein by BAL cells of patients with IPF. The dark grey boxplots represent patients who suffered from an acute exacerbation (AE, n = 12), the light grey represent patients who did’t suffer from an AE at timepoint of BAL (NoAE, n = 59) (* p<0.05, ** p<0.01, n.s. = not significant).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4295887&req=5

pone.0116775.g001: Spontaneous macrophage derived chemokine production in IPF patients w/o acute exacerbation.Boxplots of the spontaneous production of A: CCL2, B: CCL17, C: CCL18, D: CCL22, E: IL-1ra, F: TNF-α, G: IL-1β, H: IL-8 and I: CXCL1 protein by BAL cells of patients with IPF. The dark grey boxplots represent patients who suffered from an acute exacerbation (AE, n = 12), the light grey represent patients who did’t suffer from an AE at timepoint of BAL (NoAE, n = 59) (* p<0.05, ** p<0.01, n.s. = not significant).
Mentions: BAL cells of patients with IPF produced significantly more CCL2, CCL17, CCL18, CCL22, IL-1ra, IL-1β and IL-8 than cells of healthy volunteers (Table 1). There was no difference between IPF patients and controls in TNF-α and CXCL1 production. We compared the spontaneous production of macrophage derived cytokines of the patients with IPF who suffered from an acute exacerbation at time point of BAL against those patients who did not. The twelve patients with acute exacerbation had significantly higher levels of CCL2 (p = 0.002), CCL17 (p = 0.03), CCL18 (p = 0.02), CCL22 (p = 0.009), IL-1ra (p = 0.003), CXCL1 (p = 0.01) and IL-8 (p = 0.02) (Table 1 and Fig. 1). TNF-α and IL-1β were not significantly elevated, although TNF-α showed a trend towards statistical significance. Of the tested chemokines, only CCL2 correlated weakly with baseline FVC % predicted (r = -0.4, p = 0.001) and with baseline CPI (Speamans rho = -0.46, p = 0.003).

Bottom Line: 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.Furthermore, high baseline levels of CCL18 production by BAL cells were significantly predictive for the development of future AE.

View Article: PubMed Central - PubMed

Affiliation: Department of Pneumology, University Medical Centre, Freiburg, Germany.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus