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The authors of this paper observe that, "The severity of hypoxia
determines whether cells become apoptotic or adapt to hypoxia and survive.
A hypoxic environment devoid of nutrients prevents the cell undergoing
energy dependent apoptosis and cells become necrotic....During hypoxia, an
intricate balance exists between factors that induce or counteract
apoptosis, or even stimulate proliferation".
In myocytes the likelihood of devloping apoptosis appears to be
dependent upon interstitial pH increasing as the pH falls to abnormally
low levels as it does when an energy deficit develops in cells.
In an earlier communication to Heart it was asked, "Might it be
that apoptosis, an ATP-dependent process, is an altruistic sacrifice
intended to protect adjacent cells from the harmful effects of the
inflammatory response induced by free radical release and cellular
necrosis should it occur? [The absence of an inflammatory response in
apoptosis is a striking feature distinguishing it from necrosis]. Might
apoptosis even be a physiological stimulus for myocyte renewal?"
A corollary of this myocyte buddy hypothesis is that apoptotic cells
might protect contiguous cells under reductive/oxidative stress by
providing them with a supplementary supply of nutrients in times of stress
independently of an overextended blood supply. Necrosis might only occur,
and an inflammatory response be initiated, when this hypothetical
supplementary supply of nutrient fails to meet the metabolic needs of
stressed cells. [Anaerobic glycolysis is the dominant means of ATP
resynthesis in healing wounds and malignant tumours but hardly ever to the
total exclusion of oxygen. This implies that the dependence upon nutrient
relative to oxygen delivery is abnormally increased in these
What then determines the ultimate fate of cells? The studies cited
above suggest that apoptosis and/or necrosis might only occur when the
interstitial pH has fallen below 6.86 or even 6.80. In which case cells
exposed to an abnormally low pH higher than that, possibly one between
7.32 and 6.90, might be subjected to increasing cellular disorder the
effects of which could be an added risk of genetic damage and/or mutation.
This could be an evolutionary advantage in unicellular organisms and one
that might even be the product of quantum tunnelling.
Cellular proliferation is induced under similar metabolic
circumstances in an healing wound but must be accompanied by an abnormal
elevation in pH because of the reductuive biosynthesis in progress.
Angiogenesis, which also appear to be induced by the hypoxia inducible
factor 1 , is presumably a prerequisite for the delivery of adequate
nutrient to sustain the anaerobic glycolysis needed in an healing wound
and indeed tumour growth. This requires an abnormally good supply of blood
for much more nutrient must be delivered to generate 1 mol ATP by
anaerobic glycolysis than by oxidative phosporylation. A return to a
nornal tissue pH (7.40) can be expected to occur in an healed wound but
might not occur in a growing tumour. Rapidly growing tumoursmight,
however, be especially susceptible to a precipitous decline in pH induced
by an nadequate supply of nutrient and hence to the cellular necrosis
commonly seen in the center of a rapidly growing tumour.
The "intricate balance [that] exists between factors that induce or
counteract apoptosis, or even stimulate proliferation" and possibly
even invasion and metastatic spread might be defined and even determined
by the ambient pH. This appears not only to be an index of but might even
be a determinant of the metabolic environment present. The activity of
HIF-1 may even be determined by the ambnient pH which falls precipitously
in stagnant hypoxia unless preceded by cardiac arrest.
1. A E Greijer and E van der Wall
The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced
Apoptosis. J Clin Pathol 2004; 57: 1009-1014.
2. Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V,
Crittenden MD, Khuri SF. Acidosis-induced apoptosis in human and porcine
heart. Ann Thorac Surg. 2004 Apr;77(4):1376-83.
3. Richard G Fiddian-Green. A myocyte buddy system in stressed myocardium?
http://www.heartjnl.com/cgi/eletters/90/4/425#393, 2 Aug 2004
4. Jim Al Khalili. Quantum: A Guide for the Perplexed.
5. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD,
Semenza GL. Activation of vascular endothelial growth factor gene
transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996
6. Cain SM. pH effects on lactate and excess lactate in relation to
O2 deficit in hypoxic dogs. J Appl Physiol. 1977 Jan;42(1):44-9.
7. Grum CM, Fiddian-Green RG, Pittenger GL, Grant BJ, Rothman ED,
Dantzker DR. Adequacy of tissue oxygenation in intact dog intestine.
J Appl Physiol. 1984 Apr;56(4):1065-9.