Biomedical Engineering Reference
In-Depth Information
The main ligand for MAC1 is ICAM1, an immunoglobulin-like pro-
tein that is usually expressed in low numbers on the endothelial cell surface,
but is rapidly induced in the presence of inflammation (87). Vascular cell
adhesion molecule-1 (VCAM-1) is also an immunoglobulin-like molecule
expressed by endothelial cells. It binds selectively to
b
1
integrins and, in par-
ticular, to
a
4
b
1
integrin [called very late antigen (VLA)-4] on neutrophils
(88). MAC1
=
ICAM1 interactions cause increased expression of both
ICAM1 and VCAM1 on endothelial cells, suggesting that both may be
important in inflammatory driven neutrophil migration (89), and levels of
ICAM1 are raised significantly in COPD in contrast to asthma or healthy
controls and correlate with overall pulmonary neutrophil infiltration (90).
V. MIGRATION
Once the selectins and integrins have caused rolling and firm adhesion,
migration begins. This occurs preferentially at tricellular junctions (91)
and depends upon activation of platelet endothelial cell adhesion molecule
(PECAM1) (92) which is distributed both evenly around the neutrophil
and especially at intercellular junctions of endothelial cells. PECAM1 is
thought to act as a homing beacon that directs migration towards cellular
junctions, and blocking PECAM1 on either neutrophils or endothelial cells
using antibodies does not prevent adhesion but does prevent migration
through the basement membrane both in vitro and in vivo including a
PECAM1 knock-out mouse model (93-95).
Once through the endothelial cell layer, differing mechanisms may
allow diapedesis through the basement membrane and extracellular matrix.
Leukocytes bind to matrix components such as collagen and laminin via
b
1
integrins, and a series of
b
1
integrins have been found to be important in
allowing neutrophils to move through venule basement membrane and lung
tissue, with VLA-6 and -9 being perhaps the most important (96-98). It is
believed that endothelial
=
neutrophil PECAM1 interactions lead to
increased neutrophil surface expression of VLA-6 (
a
6
b
1
) (which is stored
intracellularly when cells are quiescent) and VLA-6 facilitates passage
through the basement membrane and beyond. To support this, neutrophils
from PECAM1 knock-out mice (which display poor migration following sti-
mulation with IL-1
b
) also do not have the associated rise in VLA-6, which is
seen in the wild type (95). Very late antigen-6 binds laminin (which forms a
large component of the perivascular basement membrane) and VLA-
6
=
laminin interactions may play a role in neutrophilic migration through
this tough interwoven layer (96). Subendothelial transmigration is accompa-
nied by release of neutrophil proteinases especially NE (99), which may
facilitate passage by matrix degradation, exposing laminin for VLA-6
binding. Selectin
=
integrin interactions are summarized in Fig. 2.
