Biomedical Engineering Reference
In-Depth Information
phospholipase A2 catalyses the hydrolysis and release of arachidonic acid
and then undergoes further catalysis, utilizing 5-lipoxygenase and 5-lipoxy-
genase activating protein, leading to the formation of the unstable oxidation
product Leukotriene A4 (LTA4). Leukotriene A4 is then converted to LTB4
by LTA4 hydrolase (33). The formation and release of LTB4 is upregulated
by a number of inflammatory mediators including C5a, IL-1
b
, TNF-
a
, gran-
ulocyte-macrophage colony stimulating factor, PAF, NE, and LTB4 itself
(34,35).
Leukotriene B4 is a potent neutrophil activator that acts by enhancing
neutrophil aggregation and chemotaxis (36) via by two neutrophil surface
receptors. A low-affinity receptor induces degranulation and increases oxi-
dative metabolism, whereas a high-affinity receptor induces aggregation,
chemokinesis, and adhesion via the integrin Mac-1 (37). Leukotriene B4
may also activate endothelial cell monolayers in vitro enhancing neutrophil
emigration (38), but the mechanism for this is poorly understood. Recent in
vitro studies have suggested that LTB4 is responsible for up to 45% of the
chemotactic activity of sputum from patients with COPD (39) and may inhi-
bit neutrophil apoptosis, once the cells reach the lung (40). Leukotriene B4 is
downregulated by a negative feedback loop whereby LTB4 enhances
production of degradative enzymes (35) and is inactivated by oxidation in
myeloid cells and hepatocytes, rendering it biologically inactive (41).
Levels of LTB4 have been found to be elevated in sputum (42) and
exhaled breath condensate (43) from patients with COPD. Concentrations
correlate with the degree of airway neutrophilia (44) and increase further
during exacerbations (45) with a corresponding drop once bacteria have
been successfully eradicated (46). These results suggest strongly that this
chemoattractant plays an important role in the pathogenesis of COPD.
2. C5a
C5a is derived from cleavage of complement protein C5 when the classical
complement cascade is activated. Once formed, it can bind immediately to
neutrophils in the circulation (47) and acts as a potent chemoattractant.
C5 is also produced by tissue macrophages and type II pneumocytes in the
lung (48) as a component of the alternative complement cascade. The two
pathways promote an inflammatory gradient enhancing subsequent migra-
tion. C5a has been shown to enhance adhesion molecule expression [espe-
cially intercellular adhesion molecule 1 (ICAM-1)] in airway epithelial
cells, and interestingly, this effect was exaggerated in the presence of cigarette
smoke (49). There have been few in vivo studies monitoring C5a levels in
COPD, and to date, levels have not appeared elevated in COPD patients (50).
3. Platelet-Activating Factor
Platelet-activating factor is produced by endothelial cells, macrophages,
neutrophils, and platelets during inflammatory events. It enhances neutrophil
