Acute respiratory distress syndrome is associated with impaired alveolar macrophage efferocytosis

Abstract

ARDS patients have decreased alveolar macrophage efferocytosis, which is associated with increased alveolar inflammation, and may contribute to worse clinical outcomes, including mortality. Upregulation of efferocytosis may offer a therapeutic strategy. https://bit.ly/2Q7REdM

FIGURE 1

a) Sepsis patients with acute respiratory distress syndrome (ARDS) have significantly reduced alveolar macrophage (AM) efferocytosis index compared to sepsis patients without ARDS (means 7.6 versus 22.7%; p=0.003). Error bars shown as mean±sd. Statistical analysis by Welch's t-test, n=11–12 in all groups. b) Neutrophil apoptosis assessed within 1 h of bronchoalveolar lavage (BAL) fluid collection. Sepsis patients with ARDS have significantly greater percentage of apoptotic neutrophils in BAL compared to sepsis patients without ARDS (means 41.3 versus 14.1%; p=0.0001). Error bars shown as mean±sd. Statistical analysis by Welch's t-test, n≥9 in both groups. Some patients did not have neutrophil apoptosis and necrosis measured since this was only added to the study protocol after recruitment had already begun. c) AM efferocytosis index versus BAL neutrophil apoptosis in all sepsis patients (with and without ARDS). A trend towards negative correlation was observed between AM efferocytosis and BAL neutrophil apoptosis, but this did not reach statistical significance (n=14; r=−0.525, p=0.057). Statistical analysis by Spearman's correlation coefficient. d) Neutrophil necrosis assessed within 1 h of BAL fluid collection. No significant difference in BAL neutrophil necrosis was observed between sepsis patients with or without ARDS (medians 4.5 versus 1.1%; p=0.162). Error bars shown as median (interquartile range). Statistical analysis by Mann–Whitney U-test, n≥9 in both groups. e and f) Levels of interleukin 1 receptor antagonist (IL-1ra) and IL-8 were measured in BAL from sepsis patients with and without ARDS, then correlated with AM efferocytosis index. There is significant negative correlation between AM efferocytosis index and BAL concentrations of IL-8 (r=−0.707, p=0.0003) and IL-1ra (r=−0.601, p=0.004) in sepsis patients with and without ARDS. Log scales used for both graphs, semi-log non-linear line of fit used, n=21 for both plots. Spearman's correlation coefficient with Bonferroni's correction used for statistical analysis. Bonferroni corrected significance p<0.00625. g) A threshold AM efferocytosis index of 12.7% was used to distinguish between “low” and “high” efferocytosis, based on this value being 1 standard deviation above the mean AM efferocytosis index of sepsis patients with ARDS. For all sepsis patients (with and without ARDS), low AM efferocytosis index was associated with reduced freedom from mechanical ventilation in the 30 days from enrolment (chi-squared 7.41, p=0.015). Statistical analysis by log-rank test, n=11 in each group. h) For all sepsis patients (with and without ARDS), low AM efferocytosis index was associated with decreased survival in the 30 days from enrolment (chi-squared 6.22, p=0.013). Statistical analysis by log-rank test, n=11 in each group.