Biomedical Engineering Reference
In-Depth Information
leukocrit is consistent with their key role as the first responders in the innate
immune responses of the body to infection and tissue damage [
65
].
In addition to their phagocytic mode of action, neutrophils also initiate and help
direct the repair and management of tissue damage via their release of chemokines
that recruit other white cells (e.g., monocytes, lymphocytes) to the inflammation site
[
66
]. In this way, neutrophils are critical to the acute defense of the body against
pathogens and foreign materials. Consistent with their importance to innate
immunity, neutrophils are exquisitely sensitive to inflammatory agonists. Report-
edly, only 10-100 bacterial/chemokine peptides are sufficient to dramatically
upregulate neutrophil activity levels [
67
]. Moreover, their transition from a quies-
cent to an activated state occurs within milliseconds [
67
]. Thus, a rapid neutrophil
response can be induced by low levels of inflammatory agonists.
Furthermore, neutrophils are armed with a powerful array of antimicrobial (e.g.,
reactive oxygen species, etc.) and bio-degradative agents (e.g., proteases, phos-
phatases, etc.), as well as other inflammatory mediators (e.g., cytokines) with which
they fight infection and promote tissue repair [
68
]. Release of these agents, how-
ever, may cause non-specific host tissue damage if secreted (or ''leaked'') into the
physiologic environment in excess or when unnecessary. Additionally, shutting
down neutrophil inflammatory processes during resolution stages of wound healing
and infection is also critical to ensure minimal damage to host tissues. These
features of the neutrophil are enough to suggest that cellular regulatory mechanisms
must exist to ensure tight control over the destructive potential of the polymor-
phonuclear leukocytes that, if unchecked, may cause a buildup of inflammatory
mediators that eventually damage host tissues.
But, neutrophils may also impose a more immediate effect. During acute
inflammation, neutrophil numbers in the blood rise substantially during their
recruitment [
10
]. Moreover, upon activation, neutrophils undergo rapid changes in
their geometry, deformability, and surface chemistry. Pseudopods are the most
overt morphological feature of an activated neutrophil (Fig.
1
). They contribute to
an overall increase in cell size and a more irregular cell shape [
7
]. Specifically,
pseudopods are ''cellular extensions'' that are enriched in cytoskeletal F-actin and
provide the structural basis for neutrophil membrane extension. During cell
migration, pseudopods serve as extendable anchors to aid in displacement of the
cell body [
69
,
70
]. They also serve as structural support for membrane attachments
required during the phagocytosis. Finally, they are projected by non-adherent
neutrophils to help form attachments to the vessel wall.
Along with changes in cell morphology due to pseudopod extension, neutro-
phils also display increases in their F-actin content associated with alterations to
their cytoskeletal organization [
71
]. While F-actin polymerization occurs due to
pseudopod formation, it also results from cell polarization during their transition
from a non-adherent to an adherent phenotype under inflammatory conditions.
When stimulated by pro-inflammatory agonists, neutrophils also upregulate
surface levels of cell-cell adhesion molecules that promote their rolling (e.g.,
selectins) and firm adhesive (e.g., CD18 and CD29 integrins) interactions with the
microvascular wall by binding to other leukocytes (e.g., neutrophils), platelets, or
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