T-Lymphocytes - Chronic Obstructive Pulmonary Disease - page 210

C. Consequences of the Innate Immune Reaction in the

Lungs—Peptides, Apoptosis, and Necrosis

The sustained innate immune response found in the lungs of cigarette smo-
kers (neutrophils, macrophages, eosinophils, mast cells, gd T-cells, DCs, and
maybe NK cells), and their products (cytokines, oxygen radicals, and protei-
nases) are capable of producing matrix and cellular damage. Studies in
mice have shown that after 24 hr of cigarette-smoke exposure, measurable
increases in desmosine, a marker of elastin breakdown, and hydroxyproline,
a marker of collagen breakdown, are found in BAL and their levels are cor-
related with the number of neutrophils in the BAL (11,30). Evidence of con-
nective tissue breakdown in human smokers also exists. Increased plasma
and urine levels of elastin-derived peptides and desmosine (31,32) have been
found in COPD patients when compared with nonsmokers (33-36). How-
ever, the levels of elastin-breakdown products are also elevated in smokers
without COPD (34,37-40). Smokers with rapid decline in lung function,
likely to develop COPD, were found to excrete 36% more desmosine than
low decliners (41,42). It could be concluded that proteases, probably derived
from inflammation cells, induce the breakdown of the connective tissue
network.
Despite the evidence, the concept of a protease-antiprotease imbal-
ance as the main cause for the production of COPD does not explain why
only some smokers develop COPD. It might be closer to reality to consider
the connective tissue breakdown as one of the many consequences of the
innate inflammatory reaction triggered by smoking. Furthermore, these
breakdown products or peptides could be considered as ''self-peptides'' that
could behave as self-antigens and be presented to T-cells, eventually trigger-
ing, in some smokers, a T-cell adaptive immune response against lung antigens
(autoimmunity).
There is extensive literature investigating the possible role of infectious
and environmental agents in the production of autoimmune reactions. A
common conclusion, easily applicable to cigarette smoking, is that infectious
and environmental agents have a great potential for altering self-proteins
that could then be recognized as antigens by the adaptive immune system.
Thus, a modified self-determinant could have the ability to elicit an autoim-
mune T-cell response while the self-determinant could not (42,43).
Among the important protein modifiers present in smokers are free
radicals = oxidative stress. Both nitric oxide (NO)—by itself or combined
with superoxide to form the potent oxidizing agent peroxynitrite—and other
reactive oxygen species (ROS) can be strong protein modifiers and thus anti-
gen producers. Nitric oxide and ROS may affect different cellular functions
and result in cell-death, together with mitochondrial damage, DNA strand
breaks, and structural = functional modification of proteins (43).