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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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Risk for acute exacerbation in IPF patients is dependent on spontaneous CCL18 production.A: Kaplan-Meier curves of the 59 followed-up IPF patients without AE at baseline with acute exacerbation as outcome event for two risk groups, obtained by splitting at the median CCL18 concentration (median = 10.8 ng/ml), including 95% confidence intervals (light lines). The red lines represent the group of IPF patients with a spontaneous CCL18 production levels above the median; the blue line represents the group of IPF patients with a spontaneous production levels below the median. B: Spontaneous production of CCL18 by BAL cells of IPF patients with no AE at the time point of BAL. The dark grey boxplots depict CCL18 levels of patients who developed AE during follow up, while in light grey CCL18 levels are shown of patients who never suffered from AE (NoAE) (** p<0.01).
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pone.0116775.g003: Risk for acute exacerbation in IPF patients is dependent on spontaneous CCL18 production.A: Kaplan-Meier curves of the 59 followed-up IPF patients without AE at baseline with acute exacerbation as outcome event for two risk groups, obtained by splitting at the median CCL18 concentration (median = 10.8 ng/ml), including 95% confidence intervals (light lines). The red lines represent the group of IPF patients with a spontaneous CCL18 production levels above the median; the blue line represents the group of IPF patients with a spontaneous production levels below the median. B: Spontaneous production of CCL18 by BAL cells of IPF patients with no AE at the time point of BAL. The dark grey boxplots depict CCL18 levels of patients who developed AE during follow up, while in light grey CCL18 levels are shown of patients who never suffered from AE (NoAE) (** p<0.01).

Mentions: In the multivariate analysis only CCL18 showed a significant effect after adjusting for the effect of FVC (p = 0.002). Note this effect is still significant when adjusting for multiple testing. The spontaneous production of IL-1ra, CCL2, CCL17, CCL22, TNF-α and IL-1β did not have a significant effect on event-free survival. The hazard ratio of CCL18 was similar with or without adjusting for FVC at baseline in the multivariate or the univariate Cox proportional hazard model, respectively (HR = 1.032 per ng/ml vs. HR = 1.031 per ng/ml). When defining two risk groups by splitting at the median CCL18 concentration of 10.8 ng/ml (median absolute deviation = 6.4 ng/ml), the Kaplan-Meier curves and corresponding 95% confidence intervals of the two groups differed considerable in event rates (Fig. 3A). Patients without AE at initial diagnosis, who developed AE during follow up had a significantly higher spontaneous production of CCL18 compared to patients who never had an AE (Fig. 3B).


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)

Risk for acute exacerbation in IPF patients is dependent on spontaneous CCL18 production.A: Kaplan-Meier curves of the 59 followed-up IPF patients without AE at baseline with acute exacerbation as outcome event for two risk groups, obtained by splitting at the median CCL18 concentration (median = 10.8 ng/ml), including 95% confidence intervals (light lines). The red lines represent the group of IPF patients with a spontaneous CCL18 production levels above the median; the blue line represents the group of IPF patients with a spontaneous production levels below the median. B: Spontaneous production of CCL18 by BAL cells of IPF patients with no AE at the time point of BAL. The dark grey boxplots depict CCL18 levels of patients who developed AE during follow up, while in light grey CCL18 levels are shown of patients who never suffered from AE (NoAE) (** p<0.01).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0116775.g003: Risk for acute exacerbation in IPF patients is dependent on spontaneous CCL18 production.A: Kaplan-Meier curves of the 59 followed-up IPF patients without AE at baseline with acute exacerbation as outcome event for two risk groups, obtained by splitting at the median CCL18 concentration (median = 10.8 ng/ml), including 95% confidence intervals (light lines). The red lines represent the group of IPF patients with a spontaneous CCL18 production levels above the median; the blue line represents the group of IPF patients with a spontaneous production levels below the median. B: Spontaneous production of CCL18 by BAL cells of IPF patients with no AE at the time point of BAL. The dark grey boxplots depict CCL18 levels of patients who developed AE during follow up, while in light grey CCL18 levels are shown of patients who never suffered from AE (NoAE) (** p<0.01).
Mentions: In the multivariate analysis only CCL18 showed a significant effect after adjusting for the effect of FVC (p = 0.002). Note this effect is still significant when adjusting for multiple testing. The spontaneous production of IL-1ra, CCL2, CCL17, CCL22, TNF-α and IL-1β did not have a significant effect on event-free survival. The hazard ratio of CCL18 was similar with or without adjusting for FVC at baseline in the multivariate or the univariate Cox proportional hazard model, respectively (HR = 1.032 per ng/ml vs. HR = 1.031 per ng/ml). When defining two risk groups by splitting at the median CCL18 concentration of 10.8 ng/ml (median absolute deviation = 6.4 ng/ml), the Kaplan-Meier curves and corresponding 95% confidence intervals of the two groups differed considerable in event rates (Fig. 3A). Patients without AE at initial diagnosis, who developed AE during follow up had a significantly higher spontaneous production of CCL18 compared to patients who never had an AE (Fig. 3B).

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