Endometriosis flow chart...
Agic A et al pose the question, is endometriosis associated with systemic sub
clinical inflammation? (Gynecol Obstet Invest 2006 May 4;62(3):139-147).
There is convincing evidence that the establishment of a chronic inflammatory
response, together with the presence of a local oxidative environment, could
play an important role in the etiology and the progression of several human
diseases. In the reproductive system, pathologies such as endometriosis,
polycystic ovary syndrome, tubal obstruction, preeclampsia and recurrent
abortions are related to the presence of inflammatory cytokines (TNF-, IFN-,
IL-1) and to high levels of free radicals that may damage biological molecules,
such as lipids, proteins or DNA. (Iborra A Chem Immunol Allergy 2005;88:150-162
Oxidative Stress and Autoimmune Response in the Infertile Woman)
The first flow chart (Endoflchartrev) is designed to illustrate the ubiquitous
nature of the activated PMN (neutrophil), the source of chronic inflammation, in
endometriosis, in particular via TNF alpha and free oxidizing radical
generation. The second flowchart (Endoflchart2) illustrates the role of
‘non-self’ in the maintenance of PMN activation. Given that the activated PMN is
able to initiate, maintain and orchestrate sub clinical inflammation, it is now
possible to demonstrate that endometriosis is merely a manifestation of chronic
inflammation and that as PMN activation can be controlled, the condition may be
prevented and ameliorated by such action.
See also:
Hirota Y et al Hum Reprod 2005 Dec;20(12):3547-53 Activation of
protease-activated receptor 2 stimulates proliferation and interleukin (IL)-6
and IL-8 secretions of endometriotic stromal cells.
Endoflchartrev
Click the flowchart for a fullsize image
The development of endometriosis is dependent on a predictable series of ‘mission critical’ events; stromal cell proliferation, avoidance of cell growth inhibition and apoptosis, cell migration, cell adhesion to other tissue and neovascularization and innervation.
A1
The physical manifestation of endometriosis commences with an increased stromal
cell production.
A2
In order to proceed the stromal cells must be able to evade growth inhibition
and apoptosis.
A3
Having avoided growth inhibition and apoptosis, the stromal cells must be
capable of migration.
A4
Having successfully migrated, the stromal cells must be able to adhere to
tissue.
A5
Once attached to tissue, the stromal cells require their own vasculature and
nerves.
B1
Reduced NO induces stromal cell proliferation
B2
Reduced anti-oxidants enhance stromal cell proliferation
Women with endometriosis have reduced levels of anti-oxidants.
B3 - 4
Stromal cell proliferation is also enhanced by TNF alpha and FGF.
B5
Women with endometriosis have elevated levels of iron which enhances epithelial
cell proliferation
B6
HGF increases stromal cell proliferation
C1 - 2
In order to progress to endometriosis, stromal cells must evade growth
inhibition and apoptosis. Increased Bcl2 and decreased p53 provide
anti-apoptotic environment while Bcl2 prevents IFN gamma growth inhibition.
C3
ICAM-1 is part of the mechanism by which refluxed endometrial cells escape
immuno-surveillance
D1
Endometriosis in an ectopic condition, requiring cells move from their eutopic
position. S100A13 protein is involved in cell motility as well as signaling.
D2
The production of MMP-9 and a loss of TIMP-1 are required for effective stromal
cell migration and implantation.
(Progesterone controls MMP-9 production but over-expression of TNF alpha reduces
progesterone)
D3
TIMP-1 expression is decreased in endometriosis.
E3
IL-8 stimulates the growth of ectopic endometrial cells and is implicated in the
migration of cells as it is a potent chemotactic factor
E4
IL-6 is a key element, with TNF alpha and Cox 2, in the creation of vasculature
and innervation in the endometriotic lesions particularly through its action in
stimulating the conversion, via aromatase, of androstendione into estrone and
increasing the secretion of VEGF from macrophages.
F1 – 3
In order to survive, implanted stromal cells require a vasculature.
F4
Endometriosis appears to be a hyper-estrogenic disease at the least requiring
estrogen for growth.
Estrogen also increases the production of FGF and thus enhances innervation
G1
Leptin increases the anti-apoptotic Bcl2 while decreasing the pro-apoptotic.
H1
Insulin resistance causes hyperinsulinemia and increased cortisol release and an
increase in adipocytes. Each of these conditions increases leptin production.
I1
The peptide hormone hepcidin controls the supply of iron however, hepicidin is
inhibited by hypoxia leaving iron uncontrolled.
J1
Free oxidizing radical damage red blood cells and induce rouleau clumping (see
Fig 3 and Fig 4; aaapics2.doc attached) cutting the oxygen delivery to the
muscle cell. Reduced oxygen results in a reduction of ATP generation from 36
molecules to 2 molecules per glucose molecule.
K1
Controversially, insulin resistance is the result of a group of responses that
coalesce to reduce the efficiency of muscle cell energy conversion from glucose,
fat and oxygen. As a result blood glucose and fat level are elevated and oxygen
delivery and CO2 clearance is impaired.
IRS1 receptor damage contributes to insulin resistance
K2
A loss of Glut 4 transport contributes to insulin resistance.
In addition to the loss of Glut4 caused directly by TNF alpha, resistin,
expressed by adipocytes, inhibits Glut4 activity reducing glucose uptake by 30
percent.
K3
A loss of LPL free fatty acid transport contributes to insulin resistance.
K4
Free oxidizing radicals increase the loss of Glut4 and reduce the availability
of oxygen, contributing to insulin resistance, by damaging red blood cells.
L1
NfkappaB, prompted by TNF alpha, leads to expression of ICAM-1 and a reduction
in immuno surveillance allowing stromal cells to migrate.
M1
Superoxide diminishes NO: increased stromal cell proliferation
M2
TNF alpha inhibits insulin receptors.
M3
TNF alpha (and FOR) inhibits Glut4.
M4
TNF alpha inhibits LPL.
M5
In combination with hypoxia which decreases oxygen delivery to the muscle cells,
the loss of insulin signaling, Glut4 transport of glucose across the cell wall
and LPL transport of free fatty acids, induces insulin resistance with its
effects on negative effects on stromal cell surveillance and apoptosis via
increased leptin.
The activated PMN are the largest source of FOR.
FOR increases growth and adhesion of endometrial cells in the peritoneal cavity.
M6
Cox 2 leads to the production of prostaglandin E2 (PGE-2)
M6a & b
Aromatase activity is absent in normal endometrium. In contrast, aromatase is
expressed aberrantly in endometriosis, which gives rise to strikingly high
levels of aromatase activity in this tissue
M6b1
Aromatase activity causes local estrogen biosynthesis, which, in turn,
stimulates prostaglandin E2 production by upregulating cyclooxygenase-2 (COX-2)
– positive feed back cycle (2)
M7
TNF alpha is generated by activated PMN but also by adipocytes, their numbers
increased (adipogenesis) in response to insulin resistance.
M7a
Adipocytes generate plasminogen activator inhibitor-1 (PAI).
M7a1
Adipocytes generate resistin which increases TNF alpha and IL-6 while reducing
Glut4.
M2a2
Adipocytes and insulin resistance leads to an increase in insulin that, in turn,
increases testosterone.
M2a2i
Aromatase P-450 converts testosterone to estradiol (estrogen).
M7b
PAI-1 decreases fibrinolysis allowing stromal cell adhesion and implantation.
M8
TNF alpha up-regulates VEGF
M9
Activated PMN express HFC
N1
Activated PMN use an oxidized form of ascorbic acid, DHA, as a means of
protecting themselves from their own FOR thus leaving the host in a deficient
state.
Also
Low vitamin C induces MMP
Loss of vitamin C also (1) lowers anti-oxidant status and (2) lowers NO
expression
N2
Loss of vitamin C prevents inhibition of TNF alpha stimulated NfkappaB
Progsterone and
progestational compounds attenuate tumor necrosis factor alpha-induced
interleukin-8 production via nuclear factor kappa B inactivation in
endometriotic stromal cells
A full list of supporting citations can be seen here.
They are omitted above for clarity
Although normally only regarded as a phagocyte, the PMN is capable, when
activated, of generating a substantial number of different cytokines, including
TNF alpha, IL-1, IL-6 (estrogen synthesis) and other pro-inflammatory factors
and is the largest source of FOR. It is capable of immediate activation by
elements of ‘non-self’ and can recruit further PMN (using IL-8) and up-regulate
its response to such material initiating the complement cascade (women with
endometriosis have higher C3 and C4 than non-suffering women)
Ref:
Cassatella MA Adv in Immunol 1999:73:369-509. Neutrophil-derived proteins:
selling cytokines by the pound.
Ref:
Kamer-Bartosinska A Ginekol Pol 2003 Sep;74(9):959-67 Innate immunity
participation in the pathogenesis of endometriosis