Biomedical Engineering Reference
In-Depth Information
in 1989 by Janeway and Medzhitov (13), the innate immune recognition of
microbes is based on the so-called ''pattern-recognition receptors,'' the toll
receptors, that recognize common structures in invading pathogens and
start the inflammatory reaction characteristic of the innate immunity (stran-
ger hypothesis of Janeway). However, as suggested by Matzinger (14), it is
not the presence of a microbe per se, that is important, but whether it is dan-
gerous. Matzinger proposed that during a microbial attack, it is the resulting
cellular stress or tissue damage that alerts the immune system to respond.
The previously described immune cell microdetectors (toll receptors) would
still be operational, but instead of recognizing microbe parts, they would
recognize signs of tissue distress, or molecules that are normally found only
inside cells, unless released by damage. This is now recognized as the
''danger hypothesis,'' and it has been shown that undefined cellular material
including cytoplasm, ''the intracellular molecular soup,'' (15) can activate
the immune system. Intense research in this area is showing unexpected
results. As an example, one of the components of this intracellular molecular
soup, recently identified as an alarm for the immune system, is uric acid (16),
a degradation product of nucleotides that is able to activate a central
immune player, the DC. These findings provide compelling support for
Matzinger's ''danger theory'' and a compelling explanation of how irritants,
like cigarette smoke, could trigger a full-blown innate immune response.
The present evidence suggests that, by sending ''danger'' signals in
response to cigarette smoke, the epithelium is responsible for the initiation
and possibly maintenance of the innate immune response seen in smokers.
Over 2000 different xenobiotic compounds have been identified in cigarette
smoke, and it has been estimated that there are 10
14
free radicals in each puff
of cigarette smoke (17), a considerable xenobiotic and oxidant burden on
the respiratory epithelium, which is the first line of defense to inhaled sub-
stances. Not surprisingly, the defense role comes at a price, as cigarette
smoke can harm the epithelium. Sun et al. (18) exposed human bronchial
epithelial cells in vitro to side stream cigarette smoke and found a 70%
diminution in DNA synthesis, a 44% decrease in mitochondrion activity,
and a 38% reduction of the surviving cell population. These experiments
showed that cigarette smoke is cytotoxic to epithelial cells and also that
the extent of injury was directly related to the concentration of smoke to
which the cells were exposed (Fig. 1).
There is now ample evidence to show that once injured, the epithelium
by increasing permeability and by the production of inflammatory media-
tors such as IL-8, IL-l
b
, TNF-
a
, granulocyte-macrophage colony stimulat-
ing factor (GM-CSF), ICAM-1 could be a potent stimulator of an innate
immune reaction (19,20). These epithelial changes and responses are likely
to be of pathophysiological relevance as other established inflammatory sti-
muli (O
3
,NO
2
) (21), and also infectious stimuli like hemophilus influenza
endotoxin, cause a similar release of proinflammation cytokines from these
