Macrophages - Chronic Obstructive Pulmonary Disease - page 120

species is important for the microbial killing function of macrophages; it is
also important in activating mitogen-activated protein (MAP) kinase signal
transduction pathways and the transcription factors nuclear factor- k B
(NF- k B) and AP-1, which in turn switch on multiple inflammatory genes.
Although NO is readily produced by murine alveolar macrophages, it
has proved much more difficult to demonstrate NO production and expres-
sion of inducible NO synthase (iNOS) in human macrophages in vitro.
However, NO production and iNOS expression is observed in alveolar
macrophages in vivo during pulmonary infections and alveolar NO may
play an important role in innate immunity of the respiratory tract (55).
There is increased expression of iNOS in alveolar macrophages from
induced sputum and lung parenchyma in patients with COPD (56-58). As
NO is produced under conditions of oxidative stress in COPD, this may lead
to increased production of peroxynitrite, accounting for the increase in
3-nitrotryosine immunoreactivity in alveolar macrophages from COPD
patients (56).

V. REGULATORY MECHANISMS
A. Transcription Factors

The secretion of multiple inflammatory proteins by alveolar macrophages is
largely a result of increased expression of inflammatory genes orchestrated
by proinflammatory transcription factors, such as NF- k B and AP-1. There
is increased activation of NF- k B in alveolar macrophages from COPD
patients, as evidenced by increased nuclear localization of the p65 subunit
(59) and this is further increased during acute exacerbations of the disease
(60). NF- k B may play a critical role in the increased expression of
TNF- a , chemokines such as IL-8, GRO- a and MCP-1, GM-CSF, iNOS,
proteases such as MMP-9, and adhesion molecules such as ICAM-1
(Fig. 2). LPS activates NF- k B in alveolar macrophages resulting in secretion
of GM-CSF and this is blocked by an inhibitor of NF- k B kinase-2 (IKK2)
(61).

B. Signal Transduction Pathways

The signal transduction pathways involved in macrophages activation and
secretion have not been well characterized and it is uncertain how they
are affected in COPD. The amplification of inflammatory gene expression
in COPD may be linked to abnormal activation of signal transduction path-
ways that regulate transcription factors, such as NF- k B. Endotoxin acti-
vates both the extracellular signal related (ERK) and p38 MAP kinase
pathways to stimulate expression of cytokine genes (62). PD 098059, an
inhibitor of the ERK pathway, blocks GM-CSF release induced by LPS,
but this is not affected by SB 203580, an inhibitor of the p38 pathway