Comparison of fluticasone propionate and budesonide on COPD macrophage and neutrophil function

Kylie BR Belchamber, Catherine MR Thomas, Amy E Dunne, Peter J Barnes, Louise E Donnelly Airway Disease Section, National Heart and Lung Institute, Dovehouse Street, Imperial College London, London, UK Background: Inhaled corticosteroid use is associated with increased rates of pneumonia in COPD patients. The underlying mechanism is unknown, although recent data suggest that pneumonia is more frequent in patients treated with fluticasone propionate (FP) than budesonide. Macrophages and neutrophils from COPD patients are deficient in clearing bacteria, and this might explain increased bacterial colonization in COPD. Inhaled corticosteroid may further suppress this response; therefore, we examined the effect of FP and budesonide on phagocytosis of common respiratory pathogens by monocyte-derived macrophages (MDMs) and neutrophils.Methods: MDMs from COPD patients (n=20–24) were preincubated with FP or budesonide for 1 or 18 hours, after which phagocytosis of fluorescently labeled inert beads or heat-killed Haemophilus influenzae/Streptococcus pneumoniae were measured fluorimetrically after 1 or 4 hours. Additionally, CXCL8, IL6, and TNFα concentrations in supernatants by ELISA, MDM-scavenger-receptor expression by flow cytometry, and MDM ability to kill bacteria were measured. Neutrophils from COPD patients (n=8) were preincubated with corticosteroids for 1 hour and bacteria phagocytosis measured by flow cytometry.Results: After 1 hour’s preincubation, neither corticosteroid altered MDM phagocytosis of beads or H. influenzae; however, budesonide (10-7 M) increased S. pneumoniae phagocytosis by 23% (P<0.05). After 18 hours’ preincubation, neither corticosteroid altered MDM phagocytosis of any prey, although H. influenzae phagocytosis by budesonide was significantly greater compared to FP at 10-6 and 10-5 M (P<0.05). The 1-hour preincubation with either corticosteroid inhibited bacteria-induced CXCL8 release (at 10-7 and 10-5 M, P<0.05); however, this effect was lost at 18-hour preincubation. There was no change in receptor expression, bacterial killing, or neutrophil phagocytosis by either corticosteroid.Conclusion: These data suggest that dissolved FP and budesonide do not have an overall effect on MDM or neutrophil phagocytosis of bacteria. Keywords: COPD, macrophage, neutrophil, fluticasone propionate, budesonid

Comparison of fluticasone propionate and budesonide on COPD macrophage and neutrophil function

Background: Inhaled corticosteroid (ICS) use is associated with increased rates of pneumonia in COPD patients. The underlying mechanism is unknown although recent data suggest that pneumonia is more frequent in patients treated with fluticasone propionate (FP) than budesonide. Macrophages and neutrophils from COPD patients are deficient in clearing bacteria and this might explain increased bacterial colonisation in COPD. ICS may further suppress this response; therefore, we examined the effect of FP and budesonide on phagocytosis of common respiratory pathogens by monocyte-derived macrophages (MDM) and neutrophils. Methods: MDM from COPD patients (n=20-24) were pre-incubated with FP or budesonide for 1 or 18 h after which phagocytosis of fluorescently labelled inert beads or heat-killed Haemophilus influenzae or Streptococcus pneumoniae were measured fluorimetrically after 1 or 4 h. Additionally, the following was measured: CXCL-8, IL-6 and TNFα concentrations in supernatants by ELISA, MDM scavenger receptor expression by flow cytometry, and the MDM ability to kill bacteria. Neutrophils from COPD patients (n=8) were pre-incubated with corticosteroids for 1 h, and phagocytosis of bacteria was measured by flow cytometry. Results: After 1 h pre-incubation, neither corticosteroid altered MDM phagocytosis of beads or H. influenzae; however, budesonide (10-7M) increased phagocytosis of S. pneumoniae by 23% (P<0.05). After 18 h pre-incubation, neither corticosteroid altered MDM phagocytosis of any prey, although phagocytosis of H. influenzae by budesonide was significantly greater compared to FP at 10-6 and 10-5M (P<0.05). The 1 h pre-incubation with either corticosteroid inhibited bacteria-induced CXCL-8 release (at 10-7 and 10-5M, P<0.05); however, this effect was lost at 18 h pre-incubation. There was no change in receptor expression, bacterial killing or neutrophil phagocytosis by either corticosteroid. Conclusions: These data suggest that dissolved FP and budesonide do not have an overall effect on MDM or neutrophil phagocytosis of bacteria

Human rhinovirus impairs the innate immune response to bacteria in alveolar macrophages in chronic obstructive pulmonary disease

Rationale Human rhinovirus (HRV) is a common cause of COPD exacerbations. Secondary bacterial infection is associated with more severe symptoms and delayed recovery. Alveolar macrophages clear bacteria from the lung and maintain lung homeostasis through cytokine secretion. These processes are defective in COPD. The effect of HRV on macrophage function is unknown. Objectives To investigate the effect of HRV on phagocytosis and cytokine response to bacteria by alveolar macrophages and monocyte derived macrophages (MDM) in COPD and healthy controls. Methods Alveolar macrophages were obtained by bronchoscopy and MDM by adherence. Macrophages were exposed to HRV 16 (multiplicity of infection 5), polyI:C 30μg/ml, interferon (IFN)-β 10μg/ml, IFN-γ 10μg/ml or medium control for 24 hours. Phagocytosis of fluorescently-labelled Haemophilus influenzae or Streptococcus pneumoniae was assessed by fluorimetry. CXCL8, TNF and IL-10 release was measured by ELISA. Main Results HRV significantly impaired phagocytosis of H. influenzae by 23% in MDM (n=37) and 18% in alveolar macrophages (n=20) in COPD. HRV also significantly reduced phagocytosis of S. pneumoniae by 33% in COPD MDM. There was no effect in healthy controls. Phagocytosis of H. influenzae was impaired by polyI:C but not IFN-β or IFN-γ. HRV significantly reduced cytokine responses to H. influenzae. The IL-10 response to H. influenzae was significantly impaired by polyI:C, IFN-β and IFN-γ. Conclusions HRV impairs phagocytosis of bacteria in COPD which may lead to an outgrowth of bacteria. HRV also impairs cytokine responses to bacteria via the TLR3/IFN pathway which may prevent resolution of inflammation leading to prolonged exacerbations in COPD