Inflammation in Lung Parenchyma - Chronic Obstructive Pulmonary Disease - page 22

that damage to elastic fibers initiates a repair process that rapidly restores
the fibers to structural integrity (41). Although repair mechanisms in vivo
are poorly understood, it is possible that an abnormal repair process could
contribute to the development of smoking-induced emphysema (40).
In smokers with COPD, neutrophils and macrophages may be
involved even in other features of the disease. Macrophages may be acti-
vated by cigarette smoking to release a large array of inflammatory media-
tors, including TNF- a , IL-8 and other CXC chemokines, monocyte
chemotactic peptide (MCP-1), and reactive oxygen species (19), thus contri-
buting to the development and the persistence of the inflammatory process.
With regard to neutrophils, it has been proposed that they play a role in the
mucus hypersecretion characteristic of chronic bronchitis (19). Indeed, neu-
trophil proteases, including neutrophil elastase, cathepsin G, and proteinase
3 are all potent stimulants of mucus secretion (42-44), and neutrophils are
increased in both submucosal glands and bronchiolar epithelium of smokers
(45,46). The location of neutrophils in these compartments may be crucial
for the activation of the secretory function of glands and goblet cells, and
therefore for the induction of chronic sputum production in smokers with
chronic bronchitis. The observation that, in the bronchiolar epithelium of
smokers, the neutrophilia is paralleled by an increased of goblet cells sup-
ports this hypothesis (46).
Along with macrophages and neutrophils, a crucial cell type in COPD
is the CD8 T-lymphocyte. The major activity of CD8 þ T-lymphocytes has
been considered the rapid resolution of acute viral infections, and there is
increased evidence that viral infections may play a role in the acute exacer-
bations that punctuate the progression of COPD (47,48). Moreover, the
observation that people with frequent respiratory infections in childhood
are more prone to develop COPD supports the role of viral infections in this
disease (49). It is conceivable that, in response to repeated viral infections,
an excessive recruitment of CD8 þ T-lymphocytes may occur and damage
the lung through the release of TNF- a and perforins which are involved
in lung destruction and emphysema (24,50,51). Frequent viral exacerbations
may thus contribute to the development of emphysema and therefore to the
worsening of lung function decline. This hypothesis is supported by the
recent observation that patients with COPD who suffered frequent exacer-
bations experienced a significantly greater decline in FEV 1 than the patients
who had infrequent exacerbations (52).
CD8 þ T-lymphocytes could be able to damage the lung even in the
absence of a stimulus such as viral infection, as shown by Enelow et al.
(53) who clearly demonstrated that recognition of a lung ''autoantigen''
by T cell may directly produce a marked lung injury. Taking into account
these findings, it can be hypothesized that the CD8 þ T cell accumulation
observed in COPD could be a response to an ''autoantigenic'' stimulus
originating in the lung and induced by cigarette smoking (13).