Diesel exhaust particles and macrophage function: Relevance to COPD

Abstract

Atmospheric pollution is a global problem with a significant health risk. For example, inhalation of diesel exhaust particles (DEP), a major component of atmospheric pollution, increases the incidence of exacerbations in patients with chronic obstructive pulmonary disease (COPD). DEP comprise a carbon core with adsorbed chemical compounds, metals and endotoxin. Inhaled DEP deposit in the lung and are targets for macrophages. Macrophages normally clear inhaled DEP and maintain lung sterility. However, macrophages also drive COPD pathophysiology by releasing inflammatory mediators. DEP heighten chronic inflammatory processes and induce cytotoxicity in macrophages. However the effects of DEP on macrophages from COPD patients remain unclear. The hypothesis underlying the present thesis was that 'DEP modulate macrophage pro-inflammatory mediator release and phagocytosis, and this is more prominent in COPD. To address this hypothesis, monocyte-derived macrophages (MDM) from non-smokers, smokers and patients with COPD were exposed to three types of DEP, termed DEP-N (generated from a light engine), standard reference material (SRM)-1650B, SRM-2975 and control inert beads, and MDM viability, mediator release and phagocytosis were examined. Characterisation of the DEP showed each sample to be heterogeneous in size, and subject to aggregation. Fe and Cu metals were associated with the DEP-N sample but not with SRM-1650B or SRM-2975. DEP at concentrations ≤ 100µg/ml did not induce cytotoxicity but induced apoptosis in MDM from non-smokers and patients with COPD. DEP-N, but not SRM-2975, SRM-1650B or inert beads, stimulated CXCL8 release by MDM compared with non-stimulated controls. This was not due to endotoxin in the DEP-N samples. MDM from non-smokers and COPD patients were twice as responsive to DEP-N as cells from smokers. DEP-N-treated MDM activated p38 and ERK 1/2 MAPK pathways. A p38 inhibitor (PF-755616) or MEK inhibitor (PD98059) suppressed DEP-N-induced MDM activation of p38 or ERK 1/2 respectively, with associated inhibition of CXCL8 release, with no effect on viability. DEP-N inhibited MDM phagocytosis of beads from all subject groups in a concentration-dependent manner, although inhibition was associated with decreased cell viability. In conclusion, DEP-N, but not SRM, stimulated MDM CXCL8 release and suppressed phagocytosis, possibly as a result of differences in surface-adsorbed metals. The combined, opposite functional effects of DEP may, at least in part, contribute to the association between DEP exposure and incidence of exacerbations in patients with COPD. DEP-induced CXCL8 release was mediated via p38 and ERK 1/2 MAPK pathways, which suggests that inhibition of p38 or ERK 1/2 signalling may have therapeutic potential in COPD.