Alveolar macrophages produce neutrophil
chemoattractants; this cellular cross-talk contributes to neutrophilic airway
inflammation in
chronic obstructive pulmonary disease (
COPD). We have investigated the chemotaxis cross-talk mechanisms between these cells using
COPD alveolar macrophages. Using
conditioned media from stimulated
COPD alveolar macrophages, we investigated the relative contributions of growth-related oncogene (CXCL1),
interleukin-8 (CXCL8), and regulated on activation normal T cell expressed and secreted (CCL5) to neutrophil chemotaxis and evaluated the effect of blocking the
chemokine receptors CXCR1 and CXCR2 on chemotaxis caused by macrophage-
conditioned media. Furthermore, we evaluated whether
corticosteroid treatment of stimulated alveolar macrophages inhibited the chemotaxis ability of
conditioned media. Alveolar macrophages isolated from
COPD (n = 8) and smoker (S) (n = 8) lungs were treated with ultra-pure
lipopolysaccharide in the presence and absence of
dexamethasone (1 μM). Supernatants were used for neutrophil chemotaxis assays.
SB656933 (2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-
furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-
benzamide) (CXCR2 antagonist) and
Sch527123 [1-(2-chloro-3-fluorophenyl)-3-(4-chloro-2-hydroxy-3-piperazin-1-ylsulfonylphenyl)
urea, 3-(2-chloro-3-fluoro-phenyl)-1-(4-chloro-2-hydroxy-3-piperazin-1-ylsulfonyl-phenyl)
urea] (dual CXCR1 and CXCR2 antagonist) and
blocking antibodies for CXCL8, CXCL1, and CCL5 were assessed.
Conditioned media caused neutrophil chemotaxis in
COPD and smokers (60.5 and 79.9% of total cells, respectively).
Dexamethasone did not significantly reduce neutrophil chemotaxis in
COPD or S.
SB656933 and
Sch527123 inhibited chemotaxis in a concentration-dependent manner, with the dual antagonist
Sch527123 causing greater inhibition of chemotaxis. CXCL8 antibody inhibited neutrophil chemotaxis to basal levels, although there was no significant effect of blocking either CXCL1 or CCL5 (P > 0.05). CXCL8 plays a major role in neutrophil chemotaxis caused by alveolar macrophage-derived
conditioned media, and this is most effectively inhibited by dual antagonism of CXCR1 and CXCR2.
Corticosteroids do not inhibit chemotaxis caused by macrophage-derived
chemokines.