Bacterial regulation of macrophage bacterial recognition receptors in COPD are differentially modified by budesonide and fluticasone propionate

Abstract

RationalePatients with COPD have an increased risk for community-acquired pneumonia, which is further increased by inhaled corticosteroids.ObjectiveTo assess effects of the corticosteroids, budesonide and fluticasone propionate, on macrophage bacterial responses in COPD.MethodsMonocyte-derived macrophages (MDMs) generated from blood monocytes from 10 non-smoker controls (NoS), 20 smokers without COPD (Sm), and 40 subjects with moderate to severe COPD (21 ex-smokers (COPD-ES) and 19 current smokers (COPD-S)) were pre-treated with budesonide or fluticasone (10 nM—1 μM) and challenged with live non-typeable Haemophilus influenzae (NTHI) or Streptococcus pneumoniae (SP). Cell surface bacterial recognition receptor expression (flow cytometry) and cytokine release (bead array) were analyzed.ResultsNTHI and SP reduced bacterial recognition receptor expression on MDMs from COPD and Sm, but not NoS (except TLR4). SR-AI and MARCO were reduced by both NTHI and SP, whereas other receptors by either NTHI or SP. Among COPD subjects, COPD-ES demonstrated a greater number of reductions as compared to COPD-S. NTHI reduced SR-AI, MARCO, CD11b, CD35 and CD206 in COPD-ES while only SR-AI and CD11b in COPD-S. SP reduced SRA-1, CD1d, TLR2 and TLR4 in both COPD-ES and COPD-S, and reduced MARCO and CD93 only in COPD-ES. All receptors reduced in COPD by NTHI and most by SP, were also reduced in Sm. Budesonide counteracted the receptor reductions induced by both NTHI (CD206 p = 0.03, MARCO p = 0.08) and SP (SR-AI p = 0.02) in COPD-ES. Fluticasone counteracted only SP-induced reductions in TLR2 (p = 0.008 COPD-ES and p = 0.04 COPD-S) and TLR4 (p = 0.02 COPD-ES). Cytokine release was equivalently reduced by both corticosteroids.ConclusionsReduction in macrophage bacterial recognition receptors during bacterial exposure could provide a mechanism for the increased pneumonia risk in COPD. Differential effects of budesonide and fluticasone propionate on macrophage bacterial recognition receptor expression may contribute to the higher pneumonia incidence reported with fluticasone propionate.

Benefit:Risk Profile of Budesonide in Obstructive Airways Disease

“…Due to its greater lipophilicity and tenfold higher immunosuppressant potency, the prolonged residency time of FP in the airway epithelial lining fluid compared with budesonide may result in an increased duration of local immunosuppression and impaired pathogen clearance from the airways [14, 75, 154]. Additionally, very recent work has demonstrated a differential response to budesonide compared with FP in blood-derived macrophages in smokers and ex-smokers with COPD [155]. Budesonide counteracted reductions in bacterial recognition receptors on monocyte-derived macrophages by both non-typeable Haemophilus influenzae and Streptococcus pneumoniae , whereas FP only counteracted some of the reductions by S. pneumoniae.…”

Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD

“…Preliminary results show that budesonide prevented receptor reductions induced by both S. pneumoniae and non-typeable H. influenzae , while fluticasone propionate affected only reductions induced by S. pneumoniae . 57 The authors of these reports concluded that differential regulation of immune defense genes in human bronchial epithelial cells 56 and bacterial pathogen recognition receptors on macrophages 57 may help to explain the difference between fluticasone propionate and budesonide with respect to the risk of pneumonia. Mechanisms responsible for these differences in gene regulation are not clear; however, recently, it was shown that different corticosteroids express a unique gene “fingerprint”, 58 which could explain some differences between effects of fluticasone propionate and budesonide.…”

“…In COPD, alveolar macrophages and macrophages derived from blood monocytes have an impaired ability to phagocytose and kill respiratory pathogens, which may contribute to the increased bacterial colonization in COPD. 59 – 61 In the study described above, 57 where bacterial recognition receptors in macrophages derived from blood monocytes of COPD subjects were differently affected by budesonide and fluticasone propionate, phagocytosis of bacteria was not studied. However, in the study by Taylor et al, phagocytosis of S. pneumoniae and H. influenzae by macrophages derived from blood monocytes from COPD patients was increased when cells were treated with budesonide.…”

“…The functional in vitro studies described above, 55 – 57 comparing the effects of budesonide and fluticasone propionate in bronchial epithelial cells and macrophages, were performed with dissolved corticosteroids. Thus, it was not taken into account that fluticasone propionate remains in the airway epithelial lining fluid in the form of particles for many hours after inhalation, while budesonide is dissolved within minutes.…”

Beclomethasone Has Lesser Suppressive Effects on Inflammation and Antibacterial Immunity Than Fluticasone or Budesonide in Experimental Infection Models

“…Some clinical studies have reported that budesonide has lesser effects on pneumonia risk than FP, 1 , 2 with in vitro studies suggesting that this may be related to differential effects on bacterial adhesion 9 or receptor expression. 10 We observed no difference in the ability of FP and budesonide to impair cathelicidin and increase bacterial burden. In contrast to these other studies, which have solely used in vitro experiments, we report equivalent effects of FP and budesonide both in vitro and in vivo.…”