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by Aftab J. Ahmed, Ph.D.
The Inflammatory Response
It is a safe contention that when the
history of medicine is written a few
decades yonder, inflammation will
constitute its major chunk, especially
during the earlier years of the 21st century,
for these years are being devoted to
decipher the inflammatory riddle. The riddle
is how an otherwise beneficial response
mutates into a pernicious phenomenon that
aggravates chronic diseases, if not contributing
directly to their onset.
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| Fig. 1 Inflammatory Response. A trigger (such as injury, trauma or infection) includes acute inflammatory response, which neutralizes the trigger. If the trigger does not subside, chronic inflammation results and has been implicated in autoimmune and chronic diseases and fulminant infections, such as hepatitis B, tuberculosis and schistosomiasis. |
The other face of inflammation is when it
is induced in the absence of apparent triggers,
or continues to persist after the signals
that initiate it have subsided. Since inflammatory
response can be seen as a “knee-jerk”
reaction to a physical stimulus, containing
the ensuing damage and recovering from it
necessitates almost instantaneous flow of
information to a pathogenic insult. Whereas
the natural history of inflammation is rather
well understood, it is not yet fully known as
to how inflammatory response stutters and
persists. Ordinarily, it is assumed that if an
offending stimulus is not removed, the
inflammation tends to become chronic. As
such, its ramifications are reflected in the
pathogenesis of chronic diseases. Thus,
inflammation is nearly always copresented in
an array of chronic, age-related diseases. This
bespeaks either evasive mechanisms for
unabated continuation or desensitization to
signals for control and reversal of the inflammatory
response.
How does inflammation “heal,” though?
First, it should be noted that even though
inflammation is triggered by a physical stimulus,
by and large it is mediated by the
immune response. Hence, upon an injury or
infection, a multi-factorial network of chemical
signals kicks into action. Primarily it
involves activation of leukocytes (a family of
immune cells including macrophages) and
their migration to the site of injury. This
congregation also constructs a temporary
extra-cellular matrix that forms a scaffold to
recapitulate a semblance of normal microenvironment.
Simultaneously, a family of cytokines, the
so-called molecular messengers, is produced
that essentially dictates the evolution of the
inflammatory response. For instance, the
pro-inflammatory cytokines interleukin-6
(IL-6) and tumor necrosis factor-a (TNF- )
control and mediate many aspects of inflammation.
By the same token, transforming
growth factor- (TGF-) has both a negative
and positive impact on inflammatory
response and repair of the affected tissue.
Ultimately, it is the persistence of these and
other pro-inflammatory cytokines at the site
of injury that is critical in the development of
chronic disease.
Behind this beguilingly simplistic veneer,
however, lie several cascades of reactions that
make inflammation both challenging and
evasive to intervention. To begin with, however,
inflammatory mediators IL-6 and TNF-á
set in motion two independent sequences of
reactions. On the one hand, vasoactive substances
are produced that are responsible for
redness and heat (vasodilation) and swelling
(extravasation), which are typically visible
manifestations of an on-going inflammatory
response. On the other hand, inflammatory
response primes arachidonic acid metabolism,
which bifurcates along two arms. One
arm activates the enzyme cyclooxygenase
(COX) that leads to prostaglandins, which
are the main culprits in inflammation,
whereas the other comprises a lipoxygenase
pathway that synthesizes leukotrienes and
eicosanoids.
This cursory overview illustrates the challenges
inherent to clinical management of
the inflammatory response. Given the cumulative
burden of “inflammatory” diseases,
control of inflammation is a prudent first
therapy, especially when the primary pathogenic
events are not known. Among the various
therapeutic options available, the highly
targeted TNF- therapy has proven advantageous in rheumatoid arthritis. Since TNF-á
therapy is immunosuppressive, its obvious
disadvantage is that it may increase the risk
of infections, induce allergenic response and
indeed, predispose to various types of cancers,
notably lymphoma. It is for good reason
then, that a robust chase for alternatives
continues, despite the ready availability of
short-term, albeit high-risk, non-steroidal
anti-inflammatory drugs (NSAIDS) that
inhibit the COX pathway. It turns out, however,
that there are at least two types of COX
enzymes: COX-1 and COX-2. Of these, COX-1
is more widely distributed in the body and
serves a housekeeping function by providing
modest amounts of prostaglandins to protect
the stomach, platelets, kidneys and other tissues.
It is COX-2, the second variant, which is
produced amply in cases of trauma and injury.
Aspirin is the most widely used NSAID,
and has a truly long history of therapeutic use.
For example, ancient Egyptians used myrtle
leaves as a remedy for joint pains, and
Hippocrates employed the sap of white willow
bark for pains and fever. The active principle
in both these herbs is salicylic acid, which was
first synthesized in its more potent form
(acetylsalicylic acid) as aspirin in the 1890s. It
would be several decades after its introduction
as an all-purpose pain reliever that its target
was elucidated to be COX enzymes.
Meanwhile, several generations of NSAIDS
have been designed which are chemically different
yet function similarly to reduce the amounts of prostaglandins. The use of NSAIDS
comes with a high price tag, however, in terms
of their side effects. In fact, it was arguably the
side effects that prompted the search, isolation
and, finally the availability of COX-2
inhibitors, also referred to as “super-aspirin.”
Inasmuch as NSAIDS are generic in that they
inhibit both variants of the COX enzyme, COX-
2 inhibitors are selective and specifically suppress
the action of COX-2. Lately, however,
there has been considerable controversy about
the relative benefits of both NSAIDS and COX-
2 inhibitors vis a vis their side effects,
including gastrointestinal distress, risk of heart
attack, renal load and, among others, hepatic
stress. Accordingly, considerable effort is
presently directed toward preventive measures
to tackle inflammation.
This also explains increasing use of herbals
as remedies for inflammation, especially after
the appearance of COX-2 inhibitors on the
radar screen. Thus numerous herbs have been
touted as COX-2 inhibitors, which include
turmeric, ginger, green tea, barberry, basil,
oregano and hops. While some of these show
COX-2 inhibitory activity in vitro, convincing
in vivo evidence is still unpersuasive.
Nonetheless, it could be argued that even if
sundry herbs were standardized and the
in vivo COX-2 inhibition was corroborated,
they would provide a “band-aid” solution.
Importantly, there is no evidence to suggest
that a “standardized” herbal concoction would
be devoid of side effects. This conclusion is
compelled as much by the large number of
active ingredients in an herbal admixture as by
the purported outcome. Equally, such a regimen
would hardly qualify as a nutritive, as it
would inhibit an enzyme integral to the body’s
natural defense repertoire, for, per definition, a
nutritive regimen should align itself with physiological
mechanisms not only to neutralize an
incipient danger but also take account of periinflammatory
events. That is, events that cause
trauma like infection or wound in the first
place.
Ideally then, a nutritive approach should
take account of both of these factors. Since the
immune system literally functions as a “sixth
sense” by registering the offending stimulus, it
overreaches. In so doing, it produces proinflammatory
cytokines, principally IL-6 and
TNF-, to offset the offending stimulus.
Therefore, the objective should be to keep the
immune system revved up only that long and
no more. This is because the immune system
on a hair trigger could cause far greater
collateral damage, as is evidenced by escalating
incidence of autoimmunity.
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| Fig. 2 Modulation of Cytokines by Systemic Enzymes. As a prototypical case, systemic enzymes downregulate TGF-B in subjects exposed to an inflammatory trigger. |
Since inflammation is nearly always attendant
to “wounding” of the tissue, both externally
and of internal organs, healing of the
wound produces TGF-, a turncoat for a growth factor with pleiotropic functions.
While it is indispensable in wound healing, its
continued production may cause fibrosis of
viscera and, indeed, precipitate malignancy.
Not only that, overproduction of TGF- may
well render specific treatments ineffective. The
most well-known case of that is desensitization
of the breast tissue to tamoxifen therapy.
Interestingly, proteases listed above down regulate
TGF- to well within its steady-state concentrations.
The precise mechanism by which
systemic administration of proteases accomplishes
this is yet to be fully elucidated. It can
be conjectured, however, that by restoring the
immune balance, systemic enzymes orchestrate
normalization of the inflammatory
response.
In short, systemic enzymes modulate the
immune response true to its physiological context
and, as such, are crucially instrumental in
thwarting acute inflammatory response to
degenerate into a chronic state. What is more,
systemic enzymes help dendritic cells mature
and, consequently, prime both T and B cells to
adequately counter the infectious agent, which
are either the primary pathogenic signals or
may fulminate as a result of trauma to a tissue.
Tissue damage caused by inflammation is
not merely confined to the localized accumulation
of cytokines, however. Inflammatory
response also produces an array of biomolecules
that affect other cellular functions as well.
To cite but one example, vasoactive mediators
act on capillaries, causing the endothelial cells
to adhere less tightly to each other. These same
substances make the endothelial cells surface
sufficiently sticky to trap peripatetic immune
cells passing by. The upshot is that they ooze
out of the capillaries by squeezing between the
endothelial cells. This compromises the structural
and functional integrity of the blood
vessel wall, which manifests itself as extravasation
that typically leads to inflammationassociated
edema. The bioflavonoid rutin is
among the most effective agents that
strengthen the vessel wall integrity. In addition,
rutin is also a free radical scavenger.
Alleviation of oxidative load is one of the corrective
targets in the management of inflammation,
since free radicals and reactive
nitrogen species are implicated in aggravating
the inflammatory response. Thus, the combination
of systemic enzymes and rutin could
potentially mitigate the severity of inflammatory
response.
In short, systemic enzymes present quite a
unique nutritive approach to manage inflammatory
response. Their benefits are predicated
by their mode of action. In modulating the
immune response, systemically administered
proteases function in phase with the natural
redundancy of inflammatory signals that, if
interfered with without consideration to the
biological context, complicate therapeutic
outcomes. This is illustrated by the dilemma
that the more effectively an agent suppresses
inflammation, the more likely it exposes to
infections. This lesson has been learned with
corticosteroids and further reinforced by TNF-á
neutralizing agents. This is precisely the reason
that increasingly a systems approach will figure
more prominently in the design and success of
preventive/curative modalities. Inflammatory
response is an ideal target for that. In that strict
sense, systemic enzymes provide such a
modality, albeit in its precursor form. As ongoing
research sheds more light on their mode
of action, systemic enzymes are poised to
assume a greater role as nutritives with their
impressive spectrum of health benefits.
References available upon request, send a SASE to totalhealth
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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