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by Aftab J. Ahmed, Ph.D.
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Inflammation is a Janus-faced response
for it is nearly as ubiquitous in health as
in disease. It is a tissue-based reaction
to trauma and results from integration
of a multiplicity of molecular clues in
the wake of injury and/or infection.
Inflammatory response unfolds by
conscription of specific cells and their
dispatch to the site of injury, which
removes the offending stimulus, “dissolves”
the affected surroundings and heals the
tissue.1 Quintessentially, inflammation is a
convoluted sequence of self-referential steps.
If any step in this sequence is blocked,
inflammatory response may be maintained
in a holding pattern.
Even though molecular details of the
inflammatory response are known in almost
encyclopedic detail, vexing questions persist
about inflammation as a phenomenon. For
one, it is not fully understood what signals
allow the body to make a switch to healing
the tissue amidst the “feed-forward” cycle of
inflammatory response. For say, when injury
and infection coincide, healing a wound
before the tissue is disinfected would spell
dire consequences. The timing of transition
from tissue damage to tissue healing is thus
critical. Mechanistically, the same molecular
players that trigger the inflammatory
response turncoat to begin the healing
process. Thus, tumor necrosis factor-á
(TNF- ) induces macrophages to churn out
interleukin-12 and interferon-y (IFN-y)
whereas production of pro-inflammatory
cytokines is suppressed.2 At the same time,
TGF- no longer recruits immune cell;
rather, it begins to promote tissue repair.3 As
such, the erstwhile pro-inflammatory signals now become anti-inflammatory triggers,
depending upon timing and context.
These findings impel a fundamental
conclusion—viz., that health is not necessarily
a passive outcome for a lack of proinflammatory
stimuli. Quite the contrary,
pro-inflammatory signals abound, as that is
the only way for inflammation to be primarily
a benign response. Hence it follows that
active processes must restrain an overactive
response to those insults that pose minimal
risk. This point is driven home by the
involvement of close to 50 genes at last
count, which are known to elicit the inflammatory
response, even in the absence of any
overt provocation. More importantly, a
recent report showed that a gene upstream
from those that predispose to different
autoimmune diseases might be central in the
onset of rheumatoid arthritis and lupus.
Implicit therein is the suggestion that
genetic endowment must contribute
toward the suppression of unprovoked
inflammation.
Since it is hazardous to classify genes into
pro- and anti-inflammatory groups just yet,
three essential features are forced that showcase
the beneficial aspect of inflammation.
First, circulating immune complexes and
metabolic detritus must be solubilized and
eliminated promptly. Second, a balance
must prevail in the activation, proliferation
and deactivation of immune cells mobilized
upon a pathogenic insult. Finally, the oxidative
load must be held in check because both
reactive oxygen and nitrogen intermediates
exacerbate inflammation.
Genetic complement, however, manifests
itself within the context of family history,
age, gender and localized environments, such
as intestinal flora. The impact of these
epistatic (or non-genetic) factors has been
corroborated in clinical experience. Thus,
hair-trigger inflammatory response that
makes life possible is replete with mechanistic
nuances. Embedded in these nuances
is a two-fold recognition: that the body must
launch a rapid-fire response in face of an
imminent threat. One and two, that the
body must have the ability to refrain from
doing so otherwise.4
In turn, to understand the origin of
inflammatory or autoimmune diseases, it
is essential that not only are the molecular
clues clear and crisp but also that the
pathways involved are free of any obstacles.
On the flip side of this coin, development of
anti-inflammatory remedies requires that the
complexity and multiplicity of the inflammatory
signals must be taken into account.
Celsus, the Greek philosopher and naturalist,
described inflammation as a simple
sequence of events roughly four millennia
ago. It is quite an engaging problem in signal
processing within the context of the whole
body, actually. For obvious reasons, it is also
a multibillion-dollar market for the pharmaceutical
industry. That alone adds to the
allure of anti-inflammatory regimens, preventive
or otherwise.
Aftab J. Ahmed, Ph.D., is vice president
of research and development and business
development, Marlyn Nutraceuticals, Inc.
Phoenix, Arizona.
E-mail:
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Selected references
1) Zweifach, B., Grant, L., McCluskey, R. The Inflammatory Process, Academic Press, New York, 1965.
2) Hidge-Dufour et al. “Inhibition of Interferon g-Induced Interleukin-12 Production: A Potential Mechanism for the Anti-Inflammatory Activities of Tumor Necrosis Factor,” Proc. Natl. Acad. Sci. USA. (1998). Vol. 95 p. 13806.
3) Ashcroft, et al. “Secretory Leukocyte Protease Inhibitor Mediates Non-Redundant Functions Necessary for Normal Wound Healing,” Nat. Med. (2001). Vol. 6 p. 1147.
4) Matzinger, P. “The Danger Model: A Renewed Sense of Self,” Science (2002). Vol. 296 p. 301.
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