This is a response I emailed one of the authors (Houston) of the paper,
"Anemia of Chronic Disease: A harmful disorder or an adaptive,
beneficial response?" <http://www.cmaj.ca/cgi/reprint/179/4/333.pdf>.
I've edited my remarks somewhat to remove personal references and make
them more readable. Due to size, I will probably post any sup****ting
research that's mentioned in dribbles over the next few days.
In terms of a protective mechanism in anemia, I think the place you
might want to look is HIF-1a. EPO is downstream of HIF-1a and HIF-1a
can be turned on via iron chelation. Enough EPO itself might turn off
HIF-1a via negative feedback. Metallothionein also hangs off this
pathway, as do some angiogenic factors - none of which are particularly
beneficial for cancer (although, iron chelators like tannic acid are
often used as chemotherapeutic agents). Evidence from COPD suggests EPO
itself might be protective; in the right inflammatory environment, EPO
doesn't increase red blood cell numbers [PMID 15795697, 15764763].
Recent work has shown turning on HIF-1a in the gut blocks leaky gut
syndrome (which, by the way, appears attached to cathelicidin, vitamin
D3 and autophagy - all im****tant subjects with Crohn's). Giving someone
enough EPO or iron might downregulate HIF-1a in the gut lining.
The more closely I scrutinize HIF-1a, the more im****tant it appears to
be in a network regulating a range of activities from cellular
glycolysis and mitochondrial stress response to innate immunity and
general barrier function in certain cell types (which directly addresses
your concerns about vascular permeability in sepsis). I think you're
right to point to infection rates and iron overload. I suspect you've
touched on a set of very deep relation****ps among antioxidant
management, barrier function, innate immunity and iron movement.
There's also evidence of epigenetic regulation affecting several of the
examples you cite like heart failure. And EPO/anemia treatment may not
be the only medical intervention that backfires from misunderstanding
these links - namely, broad spectrum antibiotics and glucocorticoids can
also disrupt this delicate balance.
I became interested in anemia because I've been using helminths provided
by Ovamed to control my autoimmunity (with some, but limited, success).
These helminth infections can induce anemia and I posit that this anemia
- rather than being a nasty side-effect - is central to their beneficial
function and activates the recently discovered, gut-protective HIF-1a
pathway, limiting leaky gut and autoimmunity while also activating
autophagy and synthesis of innate antimicrobials.
Since helminth infections have been a common condition in human
evolutionary history this means anemia has also been a common
adaptation. The human body may actually expect it as a regular
occurrence. Without it, certain chronic conditions could worsen in ways
for which the body is unprepared. Protective barrier function could be
compromised as par for the course of modern living, perhaps accounting
for the rash of allergies, asthma and rhinitis seen in modern society.
Hence you can see how my interest in anemia eventually brought this
paper onto my radar.
With regards to a feedback loop between EPO, hemoglobin and HIF-1a, I
have no evidence that one exists. It seems natural to posit at least an
indirect loop, but that's not very scientific reasoning. What little I
do have on the matter suggests a complicated relation****p. Acellular
hemoglobin can attenuate HIF-1a and EPO in a rat model while boosting
HO-1 [PMID 18498252] - which provides interesting implications for blood
substitutes and their effects on wound healing. The transcriptional
mechanism for the effect of hemoglobin on HIF-1a and EPO isn't entirely
clear at this point.
Perhaps cofactors are involved or there's a non-linear dose-response
curve for EPO similar to naltrexone. At a standard dose (50mg),
naltrexone blocks the mu opioid receptor but at low doses like the one I
take (4mg), it actually enhances receptor expression. (If you're
interested in the role gut bacteria play in pain perception and B cell
production, I can send you a few notes; it goes something like
lactobacillus/butyrate->mu opioid receptor->cannabinoids->B cell
proliferation; it's an unpublished link, by the way; there are papers
for each link in the chain but nothing tying it all together yet -
especially with regards to the efficacy of low-dose naltrexone for
Crohn's/M.S. or, say, how broad-spectrum antibiotics might induce
autoimmunity).
In published research, EPO doesn't always seem to elevate hemoglobin -
at least there appear to be ways to raise EPO without affecting
hemoglobin. Aside from the citations on COPD, there's a more
interesting paper on echinacea. The herbal extract boosts EPO without
affecting hemoglobin. The authors of the paper, however, omitted any
discussion linking EPO expression to innate immunity. Given re****ts of
echinacea's immunity boosting ability, this is a tantalizing link in
need of further exploration.
In a small study, patients with chronic heart failure have higher EPO
levels and lower hemoglobin than controls. Patients with more severe
cases had more severe differences from the norm but only NT-proBNP
levels predicted mortality [PMID 18664018]. Why "EPO resistance" occurs
and what it means is certainly an open question in the literature. (See
below on HDACs and heart failure.)
While there's no evidence yet linking EPO or anemia directly to innate
immune factors like cathelicidin, there is evidence linking HIF-1a to
cathelicidin production in keratinocytes [PMID 18323789], sometimes in a
bi-directional manner [PMID 18412861] - putting HIF-1a itself partially
under the regulation of the innate immune system, at least in the skin.
Given that Vitamin D3 provokes cathelicidin synthesis (as does butyrate
in some tissues), this would leave HIF-1a partially affected by the VDR
(by the way, bile acids conjugate with bacteria-produced short chain
fatty acids in the gut; some of the conjugates bind to the VDR and
activate it without elevating calcium levels like Vitamin D3 does;
there's a recent paper on lithocholic acid acetate/LCA propionate if
you're interested in this).
Cathelicidin has wide-ranging angiogenic, wound-healing [PMID 17805349],
antimicrobial and antiinflammatory properties. It's downstream of
vitamin D3/HIF-1a/butyrate and tilts mast cell inflammation towards
innate immunity [PMID 18239275]. In general, cathelicidin desensitizes
the immune system to allergic response [PMID 18768846, 17237433] by
altering TLR signaling (and given the involvement of CD44 here, I
wouldn't be surprised to see cathelicidin turn out to be central to
alopecia areata [PMID 12485450; see also PMID 12060392 and PMID
10998138]). It's curious that helminths also ****ft mast cell function
away from the spontaneous degranulation seen in allergy and other
autoimmune conditions via IgG4 secretion
<http://www.discover.com/issues/sep-93/features/ofparasitesandpo264/>).
If I might take a moment to remark on trends in contem****ary medical
research, digging in this cathelicidin/mast cell vein would certainly
fit with recent examinations of the underappreciated role mast cells
play in chronic inflammation and autoimmunity.
Cathelicidin has antiviral properties so it probably inhibits certain
kinds of cancer development, providing an additional antitumor property
for HIF-1a beyond the p53 stability you mention. I suspect cathelicidin
has antifibrotic properties under certain cir***stances. At least in
some conditions where cathelicidin is absent or underexpressed, fibrosis
does occur (e.g., cystic fibrosis [PMID 17727333]).
Heme-oxygenase 1 (HO-1 / HSP32) catalyzes the conversion of heme into
carbon monoxide and biliverdin. HO-1 is induced during hypoxia and
induced by VEGF-driven angiogenesis. It's also one of the defensive
genes induced by the Nrf2 response. Animals without a Nrf2 response
develop allergic/autoimmune syndromes. I can't find the citation at the
moment, but several heat shock proteins are induced by bacterial
colonies in the gut. HO-1 is a direct input into regulatory T-cells and
can be triggered by glutamine in the gut (that glutamine activates Tregs
is a supposition of mine; glutamine is beneficial for a number of
autoimmune bowel conditions and glutamine is known to inhibit mTOR in
the gut and induce HO-1; both HO-1 and mTOR inhibition activate Tregs;
no one has yet drawn this final connection in the literature linking
glutamine directly to Treg behavior but it's consistent with the data).
HO-1 appears to be vital for barrier function. In VEGF-induced
angiogenesis, blocking HO-1 leaves the resulting vessels leaky. Unlike
HO-1, cathelicidin does increase vascular permeability in the skin [PMID
16600571].
If anemia does wind up boosting regulatory T-cell function (say, through
HO-1), this might offer a benefit to heart attack patients whom often
have autoantibodies directed against heart muscle. Correcting anemia
could then worsen any host attack on self tissue in heart muscle. On
the other hand, boosting Tregs in cancer is a very bad idea. They
****eld tumors from the immune system - yet treating anemia in cancer, as
you mention, has blown up in the past, accelerating tumor progression.
With regards to studies on red blood cell transfusion in critical
illness and mortality, did your analysis control for the age of the
donated blood? I don't have the reference handy, but there's a recent
paper pointing to serious deterioration in donated blood after a few
days. Any study of blood transfusions and mortality will have to take
account of the freshness of the transfused cells.
Animal models ablating HIF-1alpha should shed light on its im****tance in
chronic disease states, as could ablation of her downstream actions -
metallothionein, cathelicidin, EPO, VEGF, etc. If HIF-1alpha does
account for the benefits of anemia then isolating the most im****tant
pathways downstream of HIF-1alpha could provide much more refined
benefits. For instance, metallothionein is not just a metals/pesticides
chelator but also an im****tant cellular stress response agent.
Molybdenum-based compounds might be found which efficiently induce it
without triggering more hazardous side pathways in certain diseases.
Likewise if cathelicidin provides the main benefit then there may be
vitamin D3 analogues (lithocholic acid proprionate?) that are more
appropriate.
If anemia's benefit does hinge on HIF-1alpha per se, that leaves us with
several therapeutic implications - some of which would be quite
inexpensive to apply in the developing world. HIF-1alpha inducers might
provide broad benefits for certain chronic diseases. That means
hydroxylase inhibitors being developed for leaky gut may have wide
application. Green tea components (EGCG, tannic acid) and other
polyphenol iron chelators might have broad benefits (provided there's a
source of extract untainted by fluoride and metals). Cobalt compounds
could have applications if their cancer/liver risk could be minimized.
Methylcobalamin might fit that bill - but as a nutriceutical, few
research dollars have been expended trying to explain, for instance,
methyl-B12's benefit in neuropathy (Is it due to HIF-1a???). Sketching
out this network might help avoid the detrimental hazards of EPO
administration. For instance, you might be able to break the feedback
by applying EPO with an hypoxia mimetic of some type. (I kind of doubt
this, though.)
Hypoxia induces wide-ranging epigenetic alterations [PMID 18294659].
It's possible anemia does the same, but since it's not widely assumed to
be a beneficial adaptation it hasn't been studied like this. Epigenetic
changes might account for changes in cardiac output. HDAC inhibition
sensitizes the heart to calcium signals. (There are interesting links
among viral infections, metallothionein expression, cardiac
metal/pesticide ac***ulation and heart failure. I've written an
internet article on this topic a few months back. I contacted some of
the researchers about the links but I heard nothing back from them.)
What is anemia doing epigenetically? I say that because I've already
mapped out several interesting genes in my gut under HDAC regulation:
metallothionein, defensins, cathelicidin, IDO, FoxP3 and the mu opioid
receptor (which, in turn, regulates cannabinoid signaling which, in
turn, may regulate B cell proliferation). The circadian rhythm gene,
Clock, is also an HDAC and circadian rhythms play a role in cancer
development. Circadian rhythms are frequently disrupted in severe
allergy and infection (LPS fiddles with Clock).
In tumors, HDAC inhibitors (and mTOR inhibitors) limit HIF-1a expression
and reduce angiogenesis [PMID 18519793], however normal cells may not
behave this way when exposed to HDAC inhibitors and, even if they do,
the cascade may be different when initiated from a broad response to
anemia.
When you mentioned leaky vessels in sepsis, I thought about innate
immunity once again. Butyrate upregulates defensin production and has
had a positive effect on the outcome of sepsis in animal studies. If
HIF-1a does indeed affect innate immunity in the rest of the body it
might have a positive effect on sepsis too. HIF-1a agonists coupled
with vitamin D3 and butyrate might significantly improve survival in
sepsis. Anemia could have per se antimicrobial properties via its iron
sequestration. This may represent a broad mammalian approach both to
protecting tissue against oxidative stress and guarding against
microbial infiltration. Consider the effects on iron of other mammalian
antimicrobials like lactotransferrin and lactoferrin.
When you step back a moment from the problem of anemia per se and begin
to look at the big picture of barrier function/innate immunity in
chronic disease, two other suspect interventions come into focus besides
EPO: antibiotics and glucocorticoids. Glucocorticoids damage
cathelicidin expression, at least in animals [PMID 18505188], and
antibiotics destroys the friendly bacteria needed to maintain natural
barrier function (via the butyrate/HDAC regulatory chain, HSPs, IL-10
and other factors). I think this is a fertile research area that's been
largely unexplored. It's really time bacterial management in the
western world ****fted to targeted phage therapy and quorum-sensing
intervention instead of broad-spectrum assault.
What are the long-term consequences of anemia? There has long been
evidence that mild iron deficiency reduces neurodegenerative risk and
lengthens lifespan. Several life extensionists give blood on a regular
basis for this reason. There are connections here among the
lifespan/aging-regulator klotho, ACE, Vitamin D3, mineral management,
HIF-1a, metallothionein and thymosin beta 4 / Ac-SDKP. I haven't had
time to do the research to sketch it out. There's been speculation for
years that certain ACE inhibitors might not improve mortality outcome
because of the way they interfere with klotho.
As I write this, it occurs to me that an HIF/glycolysis link might
explain why intermittent fasting depletes B and T cell levels and is so
effective for treating autoimmunity. What is the effect of fasting on
HIF-1alpha expression? What's the relation****p with cholesterol and
ketone production?
Given the role autoantibodies play in anorexia/bulimia, it's possible
anemia plays a protective role here as well. Indeed it's possible that
fasting feels good in anorexia - however otherwise detrimental - because
it's a crude attempt to shut down a harmful autoimmune reaction.
Green tea extract is a PPARalpha agonist in some tissues. It might
behave the same way in the gut. PPARalpha improves carnitine uptake in
some organs, which is downregulated in certain gut injuries. Carnitine
is required for butyrate uptake, metabolization and utilization. Hence,
PPARalpha agonists might be beneficial for Crohn's, IBD and the like -
although I've never seen speculation per se in the literature.
PPARalpha also raises the pain threshold (as does carnitine, as does PKC
inhibition... and carnitine does inhibit PKC, which might explain why;
PKCtheta in particular is vital for regulatory T-cells; PKC inhibition
also has fascinating consequences for mu opioid receptor
tolerance/dependence).
There's evidence PPARalpha is partially under the regulatory control of
HIF-1alpha or at the very least hypoxia itself [PMID 14521756].
PPARalpha and PPARgamma both act as selective breaks on angiogenesis via
actions of VEGF receptors and signaling [PMID 15828227].
Mice lacking prolyl hydroxylase PHD1 in skeletal muscle have decreased
exercise tolerance and oxygen consumption but can remarkably tolerate
ischemia in an HIF-2alpha- and PPARalpha-dependent fa****on [PMID
18316022]. In fact, loss of PHD1 reprograms glucose metabolism from
oxidative to more anaerobic ATP production through activation of a
PPARalpha pathway. Protection isn't through HIF-derived angiogenesis or
erthyropoiesis or vasodilation but rather reduced oxidative stress from
a ****ft in energy metabolism. Protection relies on HIF-2alpha and was
not observed in PHD2-deficient or PHD3-deficient mice [PMID 18176562].
PPARalpha is necessary for the antitumor activity of PEDF (pigment
epithelium-derived factor) [PMID 18497086]. HIF-1alpha may be involved
in the hypoxia-induced suppression of fatty acid metabolism in
cardiomyocytes by reducing the DNA binding activity of PPARalpha/RXR
[PMID 17963722] and there's evidence that hypoxia mimetics reduce
PPARalpha expression in murine hearts [PMID 11549245], ****fting the
heart away from beta oxidation towards glucose during hypoxia. In some
tissues, PPARs tend to rise with hypoxia [PMID 17156782].
What's the body temperature of these chronic disease patients with mild
anemia? A ****ft in basal mitochondrial metabolism could lower body
temperature and there is evidence that a dramatic lowering of
temperature in isolated heart cell studies can further activate
HIF-1alpha and HO-1, improving tissue survivability [PMID 17660400].
A PPARgamma ligand modified with an unsaturated ketone can increase cell
levels of HIF-1alpha [PMID 17658243] - unlike other PPARgamma agonists,
which ameliorate allergic airway inflammation by reducing HIF-1alpha
[PMID 16815147].
The connection between PPARs and cancer is complex and confusing [PMID
18645611].
There is evidence from old experiments in rat livers that PPARalpha
ligands can regulate iron-binding proteins like lactoferrin and
transferrin [PMID 12151626] but, by and large, I can find no evidence
this relation****p has been thoroughly explored in humans.
Fasting and calorie restriction elevate PPARalpha and carnitine
concentrations. Carnitine is needed for butyrate uptake and butyrate
activates the FoxP3 gene needed for Treg function. This is probably one
reason fasting improves autoimmune conditions. What's the effect of
anemia on carnitine content and/or PPARalpha? Carnitine does improve
EPO response [PMID 17962380], partly via HO-1. Does it reduce the
mortality associated with treating an adaptive anemia response to
chronic disease? Does EPO deplete carnitine in some manner when it's
causing adverse events? There's something going on here but it's not
clear to me what it is.
I think one of the places you want to keep your eye on is dermatology.
The skin is the easiest body barrier to study and experiment with and
usually the most neglected. Its study is often regarded as a mere step
up from cosmetic surgery, so in terms of a ****tfolio investment model
for research, results from an inexpensive investment there can be highly
profitable. HIF-1a has recently been found to be im****tant to hair
growth and cathelicidin defects play a wide range of roles in rosacea,
psoriasis and acne. I also suspect a role for cathelicidin in baldness,
an autoimmune condition which involves mast cell infiltration. Hair
follicle organs themselves contain some of the fastest dividing and
self-renewing pluripotent stem cells in the human body. Each organ
recapitulates all the signals involved in the entire HPA axis and they
are constantly regenerating the microvascular network around themselves.
Something interesting always keeps popping up in the skin literature.
Consider the role diet plays in chronic illness, especially if the gut
barrier is leaky. I've had to eliminate red meat from my diet. Liver
is particularly bad. The rich heme content does oxidize the gut lining
but red meat also contains opioid ligands. Even on low-dose naltrexone,
I still have to avoid all the foods processed by digestion into natural
opioids - red meat, wheat, milk (casein), rice and spinach. I've also
improved since avoiding turkey, I think because of its tryptophan
content. IDO degrades tryptophan and is activated by butyrate/HDAC
inhibition. Certain infections are known to manipulate IDO expression
to their advantage.
Have you considered that EPO might be damaging in mild anemia because it
improves insulin sensitivity? A course of EPO ameliorates insulin
resistance, for instance decreasing plasma cell membrane glycoprotein 1
(PC-1) expression to normal values [PMID 15209435]. Yet, insulin
resistance can be a protective strategy in the body, limiting the entry
of insulin into cells and managing oxidative stress. I'm not sure but I
think there may be something of interest in the DAF-16 fruit fly studies
of longevity or the new IRS1(-/-) mouse [PMID 17928362]. Female
IRS1(-/-) mice are longer lived despite mild insulin resistance.
Lowering signaling through IRS2 can also enhance murine lifespan by 18%.
Mice with specific IRS2 knockdown in the brain are overweight,
hyperinsulinemic and glucose intolerant but more active compared to
control mice, have greater glucose oxidation and have stable SOD2 levels
in the hypothalamus during meals [PMID 17641201]. The information on
insulin sensitivity and human longevity is complex and the field is
filled with controversy [PMID 18672019]. Insulin resistance may
represent an ongoing evolutionary adaptation that is shuffling resources
away from muscles to the brain and from large numbers of cheap offspring
to limited numbers of children requiring a greater investment [PMID
17437648].
I haven't figured out yet where to stick this last bit of information.
Heparanase is an endo-beta-d-glucuronidase necessary to angiogenesis.
Heparanase is overexpressed in the G.I. tract of Crohn's patients and
Crohn's patients often benefit from heparin therapy, which inhibits
heparanase. There is a tantalizing allergy therapy that uses
beta-glucuronidase injections coupled with antigens to induce tem****ary
tolerance (of which there is almost nothing said in the online research
literature). I'm missing one or two links in the middle but I'm sure
this set of facts is connected somehow and HIF-1a may be involved.
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