A role for homeostatic drive in the perpetuation of complex chronic illness

[Ecoclimber]

PLoS One. 2014 Jan 8;9(1):e84839. doi: 10.1371/journal.pone.0084839.
A role for homeostatic drive in the perpetuation of complex chronic illness: gulf war illness and chronic fatigue syndrome.
Craddock TJ1, Fritsch P2, Rice MA Jr3, Del Rosario RM3, Miller DB4, Fletcher MA5, Klimas NG6, Broderick G7.
Author information

Abstract
A key component in the body's stress response, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates changes across a broad range of major biological systems.

Its dysfunction has been associated with numerous chronic diseases including Gulf War Illness (GWI) and chronic fatigue syndrome (CFS).

Though tightly coupled with other components of endocrine and immune function, few models of HPA function account for these interactions. Here we extend conventional models of HPA function by including feed-forward and feedback interaction with sex hormone regulation and immune response. We use this multi-axis model to explore the role of homeostatic regulation in perpetuating chronic conditions, specifically GWI and CFS.

An important obstacle in building these models across regulatory systems remains the scarcity of detailed human in vivo kinetic data as its collection can present significant health risks to subjects.

We circumvented this using a discrete logic representation based solely on literature of physiological and biochemical connectivity to provide a qualitative description of system behavior. This connectivity model linked molecular variables across the HPA axis, hypothalamic-pituitary-gonadal (HPG) axis in men and women, as well as a simple immune network. Inclusion of these interactions produced multiple alternate homeostatic states and sexually dimorphic responses.

Experimental data for endocrine-immune markers measured in male GWI subjects showed the greatest alignment with predictions of a naturally occurring alternate steady state presenting with hypercortisolism, low testosterone and a shift towards a Th1 immune response.

In female CFS subjects, expression of these markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation.

These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis.

Though coarse, these models may nonetheless support the design of robust treatments that might exploit these regulatory regimes.

 

[Snow Leopard]

Its an interesting attempt. All models like this fall well short of describing real systems, but I think such modelling could be useful in a serious research programme. Unfortunately no one is funding such a programme (basically measure stuff, build model, use model to make predictions on stuff to measure, revise, etc).

Of note, this model explicitly denies the possibility of male CFS being caused by a hypocortisol state:

Our analysis of these coarse grained models spanning across multiple regulatory axes highlighted the important role of gender in supporting a persistent hypocortisolic condition. Due to the suppressive actions of the male gonadal system in regulating itself and the HPA axis, a low cortisol steady state is never available to the male, at least theoretically at this level of detail.

One of the main criticisms I have with this paper and the previous models by these authors is that they fail to explain the real dynamic range of real expression of GR, cortisol. Eg the recent Light et al study which found GR expression to be normal at rest, but abnormal in patients after repeat exercise.

 

[Snow Leopard]

The conclusion is nice:

Finally, when considering alignment with the experimental data presented here for CFS and GWI, it is important to remember that it was never our hypothesis that these illnesses resulted solely from the actions of homeostatic drive. Instead we proposed that homeostatic drive might be a significant contributor to the persistence of illness mechanisms. Because these naturally occurring regimes, once instantiated, provide an alternate stable homeostasis resistant to change, it may offer fertile ground in support of many chronic pathological processes. The alignment of several immune and endocrine markers modeled here with experimental data from CFS and GWI, two chronic conditions, would support at least partial involvement of the body's own homeostatic drive in facilitating the perpetuation of these conditions. Correlation between these illness conditions and predicted stable states does not imply causation. These results do not suggest that homeostatic drive is the root cause of GWI or CFS, only that it might serve to sustain these chronic illnesses. This may promote resistance to therapy and the natural regulatory barrier to change, even positive change, should at least be considered in the design of robust treatment avenues. Knowledge of the basins of attraction identified by the modeling methods presented here can provide a comprehensive overview of multisystem dysregulation. This knowledge may be used to identify multiple therapeutic targets to be treated in conjunction to correct overall system imbalance. This opens the possibility of discrete interventions targeting multiple systems where treatment could eventually be discontinued, leaving normal regulatory drive to return the system to the correct resting state. This is very different from conventional long-term administration of a drug regimen, whereby the system is held artificially in a more desirable, but unstable state through continued intervention.

That seems to be an alien concept for the treatments of chronic illnesses today!

 

[Ecoclimber]

Someone is thinking out side the box

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A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome

http://A Role for Homeostatic Drive...Gulf War Illness and Chronic Fatigue Syndrome