Good to have new blood. One tends to fall into one's particular rut and newcomers help us climb out with new ideas.

My own "rut" is the idea of pre-natal exposure to LPS setting the stage for later development of PD as environmental hits accumulate over the years. Liu and Hong at the NIH and Carvey at Rush in Chicago have published some interesting stuff and it makes sense. One of the disquieting things they found was that a single exposure to LPS could activate already "primed" microglia and that they would still be in that state months later without further exposure.

PWP have an added burden of chronic elevated cortisol levels. I once thought that to be the result of another mishap in the womb, but now lean to it being an attempt to control the inflammation noted above. If that chronic state eventually leads to some sort of hypersensitivity to the chemical brew tied to the stress response, then it could explain why we are so maddeningly stress sensitive.

Don't intend to pontificate. Just thought I'd give you an opening or two for further discussion. Welcome.

Hi there, repeated exposure to threats like LPS will indeed increase sensitivity and damage through stress though let say 'allergic' type responses. So what you are proposing might well be one contributing mechanism for the disease.

AT1 induced inflammation will play a part in this scenario too. AT1 expression occurs through both extra cellular and intracellular stress sensing mechanisms.

Hypoxia through HIF-1alpha within the cell causes AT1 mRNA to be produced.

The oxidative sensing pathway is through oxidised LDL acting on scavenger receptors like LOX-1 (Lectin like oxidised LDL receptor) also causing AT1 to be expressed.

Activation of AT1 by its agonist Angiotensin II causes the production of the full spectrum of proinflammatory mediators including TNF-a, COX-2, IL-1b, TGF-b as well as NAPDH oxidase which promotes yet more oxidative stress.

The nasty part is that once you immune system is suppressed by a 'wound' that wont heal, you are open up to yet more co-infections that will take advantage and worsen the situation.

I'm ignorant of what AT1 is, unless it is angiotensin1, the precursor of angiotensin II. Having worked and published in the area of hemostasis, I am used to "AT" as the abbreviation for antithrombin, as in antithrombin III.

Also, I'm unaware of the intracellular response to HIF1-alpha of stimulating transcription of AT1,(whatever it is). Can you give a literature reference for this?

From "Cancer, inflammation and the AT1 and AT2 receptors" by one Gary Robert Smith and Sotiris Missailidis

"The critical role of inappropriate inflammation is becoming accepted in many diseases that affect man, including cardiovascular diseases, inflammatory and autoimmune disorders, neurodegenerative conditions, infection and cancer.
This review proposes that cancer up-regulates the angiotensin II type 1 (AT1) receptor through systemic oxidative stress and hypoxia mechanisms, thereby triggering chronic inflammatory processes to remodel surrounding tissue and subdue the immune system. Based on current literature and clinical studies on angiotensin receptor inhibitors, the paper concludes that blockade of the AT1 receptor in synergy with cancer vaccines and anti-inflammatory agents should offer a therapy to regress most, if not all, solid tumours.
With regard to cancer being a systemic disease, an examination of supporting evidence for a systemic role of AT1 in relationship to inflammation in disease and injury is presented as a logical progression. The evidence suggests that regulation of the mutually antagonistic angiotensin II receptors (AT1 and AT2) is an essential process in the management of inflammation and wound recovery, and that it is an imbalance in the expression of these receptors that leads to disease.
In consideration of cancer induced immune suppression, it is further postulated that the inflammation associated with bacterial and viral infections, is also an evolved means of immune suppression by these pathogens and that the damage caused, although incidental, leads to the symptoms of disease and, in some cases, death.
It is anticipated that manipulation of the angiotensin system with existing anti-hypertensive drugs could provide a new approach to the treatment of many of the diseases that afflict mankind."
http://www.pubmedcentral.nih.gov/art...?artid=1074345

My first question is how do the AT1 and AT2 recptors relate, if at all, to the T1 and T2 responses of the immune system?

are both the bane and blessing of scientists (and those who try to read their writings).

Gary (Robert), pardon the ignorance of a protein chemist who dabbles in neuroscience. I now remember having read about the AT1 and AT2 angiotensin receptors somewhere in the past.

Rick, The T1 and T2 in immunology are designations of particular functional types of lymphocytes. The "T" designation refers to their originally being tought to originate in the thymus, or another immune organ in chickens starting with a T (which I can not recall just now).

Robert (Lewis) Smith

So the similarity of the acronymns is coincidence? Good, I can sleep tonight.

Hi there.

Thanks for allowing me to participate.

Here is a very quick overview of Angiotensin:

Angiotensin II (Ang II) is a peptide hormone within the Renin-Angiotensin System (RAS), generated from the precursor protein angiotensinogen, by the actions of renin, angiotensin converting enzyme, chymases and various carboxy- and amino-peptidases.

The RAS plays a part in maintaining blood pressure, water and electrolyte homeostasis and drugs have been developed to manipulate this system and lower blood pressure in the treatment of cardiovascular diseases. Angiotensin Converting Enzyme (ACE) Inhibitors, that are now in widespread use, block the production of Ang II but in some cases coughing is caused due to activated Bradykinin. Angiotensin Receptor Blockers were specifically developed to avoid this side effect by blocking the Ang II Type 1 receptor (AT1).

Angiotensin I (Ang I) is cleaved by ACE into Ang II (Ang II), which then binds to angiotensin receptor type 1 (AT1) and type 2 (AT2).

The opposing roles of its two mutually antagonistic receptors AT1 and AT2 are now well established in cardiovascular disease. It is, however, becoming recognised that the RAS (in particular the AT1 receptor which is the main effector of the system) is a key mediator of inflammation in cells that are under stress, with the expression and activation of AT1 receptors causing the transcription of many inflammatory factors that coordinate a stress (or wound) response....

Hi guys.

I've been doing a few searches on pubmed and although I suspected it before I'm pretty convinced that infections play a big part in the progression of the disease.

I also dont think its just one infection. Once the immune system is suppressed through chronic inflammation, chances are that other infections will take advantage.

PMID: 16528677 Infection, Inflammation and PD
PMID: 16160463 Pressure ulcers: more lethal than we thought?
PMID: 16104942 Role of chronic infection and inflammation. Part 1: eradication of Helicobacter in the cachexia of idiopathic parkinsonism.

I cant post the link, but try a search on google for

"New ideas about the cause, spread and therapy of Lyme Disease"