Biomedical Engineering Reference
In-Depth Information
CXCL8 is produced by both leukocytes (monocytes, T cells, neutro-
phils, and natural killer cells) and nonleukocytes [endothelial cells, fibro-
blasts (56), and epithelial cells]. Production is not constitutive but is
induced by proinflammatory cytokines such as IL-1
b
and TNF-
a
(59), bac-
teria such as Pseudomonas aeruginosa (60), bacterial products such as LPS
(22), viruses such as adenovirus and rhinovirus (61,62), and oxidants from
cigarette smoke (63). CXCL8 is produced as a precursor protein and is
processed into its active form by proteinases released from CXCL8-secreting
cells, predominantly the neutrophil (64).
Once secreted, CXCL8 binds to CXC receptors (1 and 2) on leuko-
cytes. The G-protein receptor is then converted to the GTP-bound form
and dissociates into G
a
and G
bg
subunits. The G
bg
subunit initiates a phos-
phate pathway resulting in activation of protein kinase B and GTPases,
which leads to enhanced neutrophil adherence to endothelial cells (by
increasing expression of
b
2
integrins) and directed cell migration (Fig. 1).
CXCL8 also activates Ras and eventually mitogen-activated protein kinases
and extracellular signal-related kinases in neutrophils, causing degranula-
tion. These effects can be downregulated by intracellular regulator of
G-protein signaling (RGS) proteins that decrease the half life of the active
GTP-bound state of CXCR, leading to reduced CXCL8-induced neutrophil
migration and adherence (65).
In COPD, sputum CXCL8 correlates with levels of neutrophil activa-
tion markers such as MPO and NE (66) and is proportional to airflow
obstruction (67). It is believed that oxidative stress caused by cigarette
smoke and bacterial and viral infections induce CXCL8 production in both
airway epithelial and endothelial cells, leading to neutrophil adhesion, che-
motaxis, and degranulation.
In addition to CXCL8, at least five other CXC chemokines mediate
neutrophil responses in humans and are believed to be important in COPD;
three forms of growth-related oncogenes (GRO) (
a
,
b
,and
g
), epithelial cell
derived neutrophil-activating peptide (ENA)-78, and neutrophil-activated
peptide-2. GRO
a
is detectable in bronchial secretions (68), and both GRO
a
and ENA-78 have been measured in BAL fluid (69). Neutrophil-activated
peptide-2 is produced following stimulation of pulmonary microvascular
endothelial cells (70) although it has not yet been identified in human alveo-
lar or bronchial fluid. A number of other inflammatory mediators including
fragments of fibrin, elastin, and collagen are also neutrophil chemoattrac-
tants in the lung.
As stated, studies have demonstrated high levels of CXCL8, LTB4,
and GRO
a
in bronchial secretions from patients with COPD (66,68,71).
However, their presence does not necessarily mean they play a central role
in neutrophil migration in this disease. The contribution of CXCL8 and
LTB4 has been demonstrated in vitro studies utilizing IL-8 monoclonal
antibodies and LTB4 receptor antagonists. Here, neutrophil chemotaxis
