Neutrophils - Chronic Obstructive Pulmonary Disease - page 143

uniformly expressed on neutrophils, and binding occurs after and is more
long lived than L-selectin-ligand interactions. In the presence of other adhe-
sion molecules, P-selectin = PSGL1 binding slows neutrophil rolling velocities
and eventually causes cell tethering to the endothelium, but in the absence of
other adhesive events, binding is also transient (80).
E-selectin is not stored, but requires gene transcription for expression
with peak expression occuring 4-6 hr after initiation of inflammation (81).
In animal studies, E-selectin binds to E-selectin ligand 1, although the
human ligand remains uncharacterized (52). It is thought to maintain
neutrophil tethering after P-selectin has been down regulated. E-selectin
expression is increased in both serum and BAL in patients with COPD
and correlates significantly with lung function (82).

2. Firm Adhesion

Firm adhesion is thought to be possible only in the presence of inflamma-
tory stimuli. Once L-selectin and PSGL1 are bound and activated, signal
transduction pathways lead to the sequential activation of integrins, through
which firm adhesion occurs (73,83).
The integrins are heterodimeric transmembrane glycoproteins that
comprise an a and b subunit, which together form an extracellular binding
site. Integrins are found on many hematopoietic cells, with differing a and b
subunits. The two most important integrins in neutrophil migration through
endothelial cells share a b 2 subunit (CD18), these are macrophage antigen
1 (MAC1; CD11b = CD18) and lymphocyte-associated function antigen 1
(LFA-1; CD11a = CD18), with MAC1 being of the greatest importance.
A third CD18 integrin, p150,95, can also promote neutrophil trafficking,
but has been less well studied.

3. MAC1

Preformed MAC1 is stored in PMNs in secretory vesicles and specific and
gelatinase granules (54,84) and is rapidly mobilized to the cell surface after
exposure to inflammatory stimuli (including fMLP, TNF- a , and LPS).
Inflammatory stimuli also promote transcription and translation of the
MAC1 gene via a G-protein Rho (85), increasing expression during inflam-
mation (52). Some MAC1 are expressed constitutively on the neutrophil,
but these proteins are incapable of binding ligands unless activated by intra-
or extracellular signals, where conformational changes occur exposing a
requisite binding epitope (86). This is an important consideration in experi-
mental work, as measured MAC1 does not necessarily equate to function-
ally active MAC1. However, neutrophils from patients with COPD have
increased baseline surface expression of MAC1, which increase further
following activation (7), suggesting that this adhesion molecule may play
a role in the pathogenesis of the disease.