Inflammatory Mediators - Chronic Obstructive Pulmonary Disease - page 255

The PGE 2 is a bronchodilator of human airways (8), inhibits the
release of proinflammatory cytokines from monocytes (9) and acetylcho-
line release from airway cholinergic nerves (via EP 3 receptors) (10), sug-
gesting that it may have beneficial effects in COPD airways.
Furthermore, PGE 2 markedly enhances the anti-inflammatory actions of
phosphodiesterase-4 (PDE4) inhibitors which are in clinical development
as anti-inflammatory therapy for COPD (11). However, PGE 2 also has
potentially detrimental effects in stimulating mucus secretion and expres-
sion of mucin genes (MUC5AC, MUCB) (12) and in sensitizing and acti-
vating airway sensory nerves to enhance coughing (13,14). Inhalation of
the nonselective COX inhibitor indomethacin is reported to reduce mucus
hypersecretion in patients with COPD (15), but long-term trials of
COX inhibitors (and in particular COX2 inhibitors) have not yet been
undertaken.
The PGF 2 a is also increased in exhaled breath condensate of COPD
patients (3). The PGF 2 a is a bronchoconstrictor and also activates airway
sensory nerves to produce cough (16).

B. Leukotrienes

Human alveolar macrophages express cytosolic phospholipase A 2 and
release leukotriene (LT)B 4 and platelet-activating factor on activation
(17). The LTB 4 is increased in exhaled breath condensate of patients with
stable COPD (3) (Fig. 2) and is further increased during exacerbations
(18). The LTB 4 is also increased in the sputum of patients with COPD,
particularly during exacerbations (19,20). Plasma concentrations of LTB 4
are also reported to be increased in COPD patients (21). The cellular source
of LTB 4 in COPD is likely to be from alveolar macrophages, airway epithe-
lial cells, and neutrophils.
The LTB 4 is a potent chemoattractant of neutrophils through the acti-
vation of BLT 1 receptors that are expressed predominantly on neutrophils.
The BLT 2 receptors are expressed on T-lymphocytes (22).The BLT 1 antago-
nists, such as LY29311, have now been developed for the treatment of
neutrophilic inflammation (23). The BLT 1 -receptor antagonists inhibit the
neutrophil chemotactic activity of sputum from COPD patients, indicating
the potential clinical value of such drugs (20,24), but only give about 25%
inhibition indicating that other neutrophil chemotactic factors are also
involved. The LTB 4 antagonists have also been shown to reverse lipopoly-
saccharide-induced survival of neutrophils from COPD patients (25).
Cysteinyl-leukotrienes are increased in asthma and largely derived
from mast cells, but there is no evidence that they are increased in COPD.
Thus, exhaled breath condensate shows an increase in concentration
of cys-LTs in adults and children with asthma, but not in patients with
COPD (3,26,27).