Neutrophils - Chronic Obstructive Pulmonary Disease - page 139

adhesion and acts as a chemoattractant (51), but there have been no studies
specifically examining this chemoattractant in COPD.
4. Formyl-methionyl-leucyl-phenylalanine

The tripeptide fMLP is present at the amino termini of proteins from most
types of bacteria, but is not found in proteins of human origin. It is released
during bacterial degradation and binds to seven transmembrane-spanning
G-protein coupled receptors on neutrophils and monocytes. The fMLP-
receptor interactions activate multiple transduction pathways enhancing
neutrophil adhesion and chemotaxis [via cytoskeletal changes (52)], exocyto-
sis of secretory granules and superoxide anion production (for a review, see
Ref. 53). Formyl-methionyl-leucyl-phenylalanine is a powerful chemoattrac-
tant, resulting in cell migration and degranulation and therefore potentially
increased tissue disruption. The fMLP receptors are expressed on quiescent
neutrophils, but expression is increased once they are activated, following
the mobilization of secretory vesicles (54). A recent study compared fMLP
receptor numbers on peripheral neutrophils from subjects with COPD,
healthy smokers, and healthy nonsmokers. Levels of receptors were elevated
in both healthy smokers and subjects with COPD who smoked, but not non-
smoking patients with COPD (55), which suggest that fMLP may play a role
in the development of disease and its progression during smoking, especially
during bacterial exacerbations.

5. Chemokines

Chemokines are a family of approximately 40 structurally related soluble
cytokines that exhibit chemotactic activity for a limited spectrum of leuko-
cytes. Chemokines are low molecular weight proteins with cysteine at well-
conserved positions that exhibit a basic charge and have an affinity with
heparin (56), and they bind to cell-surface G-protein coupled receptors with
seven transmembrane domains (56,57). Chemokines also bind to proteogly-
cans on vascular endothelium and to extracellular matrix proteins in the
tissues forming an immobilized gradient of chemokine concentration that
begins at the venular endothelium, rises through the tissues, and peaks
at the site of injury.
Chemokines are classified by the sequence of NH 2 -proximal cysteines.
There are four subgroups: C, CC, CXC, and CX 3 C chemokines, where ''X''
is any amino acid placed between the cysteine groups. CXC chemokines are
further divided depending on the presence (ELR þ ) or the absence (ELR )of
the tripeptide motif Glu-Leu-Arg at the NH 2 terminus before the first
cysteine (57,58). ELR þ CXC chemokines bind both CXC receptors 1 and
2 (CXCR1, CXCR2) with high affinity and are potently chemotactic for
neutrophils and exhibit angiogenic activity. Interleukin-8 (now called
CXCL8) is the most important (ELR) þ CXC chemokine in the development
of COPD.