Biomedical Engineering Reference
In-Depth Information
Figure 3
Integrating chemotactic signals. Neutrophils migrate away from one che-
moattractant source towards another. Photographs of the stained neutrophils after
2-hr migration towards a distant source of LTB4 or interleukin 8 referred to here
as IL-8 (1 pmol) in the presence or absence of an inverse gradient generated by
LTB4 or IL-8 (10 pmol). Cells placed with one agonist migrate towards the other
agonist almost as well as control cells, but do not migrate well towards a distant
source of the same agonist. (Reproduced from Ref. 100 with kind permission.)
components (111). Furthermore, neutrophils from mice whose genes for NE
and CG had been ''knocked out'' showed normal migration both in vitro
and in vivo when exposed to LPS, although pathogen clearance was
impaired (112) and mice deficient in gelatinase B have normal neutrophilic
migration into the lungs (113). However, animal studies of cigarette smoke
inhalation suggest that neutrophil influx into the lung is reduced in the pre-
sence of proteinase inhibitors. Guinea pigs exposed to cigarette smoke
demonstrate an acute response composed of an airway neutrophilia and
an increase in connective tissue breakdown products found in BALF, and
both of these responses are reduced by pretreatment with synthetic NE inhi-
bitors (114). Intratracheal instillation of a synthetic NE inhibitor reduced
neutrophil influx triggered by elastase, but only intravenous instillation of
the inhibitor prevented the increased airway neutrophilia seen in response
to sputum from patients with cystic fibrosis (115).
In humans, two syndromes provide clues as to the importance of pro-
teinases in neutrophilic migration. In Papillon-Lefevre syndrome, patients
have a deficiency of dipeptidyl peptidase 1 that causes a functional defi-
ciency of NE and CG via impaired processing of enzyme precursors. Here,
neutrophil migration is impaired, but the main phenotype is periodontitis
alone, with no systemic features of immunodeficiency (116). Chediak-
Higashi syndrome is associated with deficiencies in NE, CG, and PR3,
and here neutrophils do not migrate towards chemoattractants (117) again
suggesting that proteinases play a role in cell migration.
This conflicting evidence suggests that migrational dependence on
proteinases may vary according to stimuli and the scientific model used.
In addition, if neutrophil migration is partially proteinase dependent, migra-
tion may not require degradation of extracellular matrix substrates by pro-
teinases to allow cell passage, but instead the generation of inflammatory
chemokines and cytokines or modulation of adhesion molecules [enhancing
