Image by Rudy and Peter Skitterians from Pixabay

In Part One of this article, I described the three phases of the Cell Danger Response, a cycle in which cells take themselves “offline” from the rest of the body in order to protect themselves from a threat, and to repair. CDR1 involves a shift from energy production to oxidative stress, in order to fight off the invader. CDR2 involves tissue proliferation for healing. CDR3 involves new cell differentiation, connection to neighboring cells, and re-establishes normal cell metabolism and sensitivity to outside signals. (I’d suggest reading part one before going on to this one.)

How Cells Get “Stuck” in One of the CDR Phases

The healthier and more “vital” the person or the tissue, the more readily injured cells can enter and complete the CDR cycle with total resolution. But if any cells fail to complete the cycle and reintegrate, this might create a “weak link”—susceptible to later injury.

I often express this to patients like this: “Whenever you get stressed, whatever your weak link is, breaks.”

On a systemic level, re-exposure to a toxin your body has seen before tends to trigger a faster and more extreme response than the first time. I see this most often with CIRS (Chronic Inflammatory Response Syndrome) from biotoxins.

Chronic CDR1 Activation

Cells can get stuck in CDR1 due to ongoing inflammation from a real ongoing threat (you’re still in a toxic environment, or you still have an infection), a perceived ongoing threat (MPO chronic over-activation fits here), or chronic hypersensitivity of the (purinergic) receptors that first responded to the extracellular ATP.

Sometimes the oxidative stress involved in normal CDR1 initiation can actually damage the enzyme needed to shut CDR1 off. This may happen when the CDR gets initiated in an already inflamed environment—such as in cardiovascular disease and metabolic syndrome. In these cases, the oxidative damage secondary to the metabolic problem might be prevent resolution… and thus, building blocks for membrane repair (phosphatidylcholine and essential fatty acids) might be beneficial.

Exercise has also been shown to help regulate that enzyme that shuts the CDR1 off (called CD39)—so this can be a meaningful intervention at this stage. Quercetin and resveratrol also help to regulate CD39, as do T-regulatory cells (Tregs). The most relevant supplement that modulates Tregs in this capacity is Vitamin D.

Adenosine (a breakdown product of used ATP that accumulates throughout the day) also boosts CD39 production. Caffeine notoriously blocks adenosine receptors — so if someone stuck in CDR1 drinks coffee or another caffeine source, it might be worth taking a holiday from it for a few weeks, to clear out the pipes and re-sensitize the adenosine receptors.

Already damaged mitochondria can also trigger ongoing oxidative stress, which can damage the CD39 enzyme. I suspect selective antioxidants that might clean up excessive ROS might shine here, such as molecular hydrogen. Traditional mitochondrial supplements tend to favor oxidative phosphorylation, which is inappropriate at this step, and Naviaux noted that it can in some cases even make things worse.

Assuming the original insult is gone, Low Dose Naltrexone can really shine at resetting a chronic stress response too.

According to Naviaux, diseases that fit a chronic CDR1 activation pattern include CIRS, chronic infections of all kinds, allergies, and asthma.

Chronic CDR2 Activation

The tissue proliferation phase might go awry if mature cells attempt to revert back to stem cells, but fail—then they can become senescent (zombie) cells. A few of these can still be beneficial to the overall process, triggering inflammatory cytokines that help to perpetuate healing. But too many of them can halt the cell danger response cycle, and it can get stuck here. If this is the case, fasting can be helpful, to trigger autophagy.

Warburg metabolism characteristic of CDR2 occurs in the presence of oxygen that isn’t explicitly used for ATP production, and this extra oxygen appears to be part of the signaling process for tissue remodeling and regeneration—which implies that hyperbaric oxygen (HBOT) can be helpful if someone is locked in unresolved CDR2. (However, as excessive reactive oxygen species characterize CDR1, HBOT can potentially be harmful if someone is stuck in this phase, rather than in CDR2.)

Because Warburg metabolism runs on glucose, someone “stuck” in this phase might do well on the ketogenic diet, to switch the metabolic fuel from glucose to fat.

According to Naviaux, diseases that fit a chronic CDR2 activation pattern include metabolic disorders (diabetes, HTN, heart disease, peripheral vascular disease, elevated uric acid, fatty liver, etc), some fibrotic disorders (pulmonary fibrosis, keloids), Irritable Bowel Disease (Crohn’s, Ulcerative Colitis), and cancers.

Chronic CDR3 Activation

The tissue remodeling phase may fail to progress to resolution if the “we’re all done now” signal fails. What this looks like depends upon what the tissue is supposed to do. But ultimately, it means the tissue is no longer actively inflamed, and no longer actively remodeling either—it’s just not functional. This might occur due to senescent cells that made it through CDR2, but DNA damage renders them non-functional.

Since the parasympathetic nervous system is required to send the “all clear” signal, treatments that stimulate the vagus nerve are indicated here, even in the absence of overt dysautonomic symptoms. Nicotine patches might also be useful for this population for the same reason, though that is speculative. But also along these lines – healthy social connections and support are huge for sending safety signals to the body.

Specialized pro-resolvin mediators (SPMs) also fit here: their whole purpose is to clear out the metabolic waste left over after a conflict, so that resolution can occur.

Direct mitochondrial support is more likely to be useful here too —including red light therapy, to try to restore normal oxidative phosphorylation.

According to Naviaux, diseases that fit a chronic CDR3 activation pattern include neuropsychiatric conditions (autism, OCD, anxiety, depression, bipolar, schizophrenia, PANS, PANDAS, Parkinson’s Disease, Alzheimer’s, Multiple Sclerosis, Tourette’s Syndrome, ALS, TBIs), many autoimmune conditions (Lupus, scleroderma, Sjogren’s, Polymyalgia rheumatica, Ankylosing Spondylitis, Hashimoto’s, Rheumatoid Arthritis), chronic pain syndromes (fibromyaltia, allodynia, complex regional pain syndrome), eye diseases (macular degeneration, presbyopia, presbycusis), chronic migraines and headaches, psoriasis, eczema, and more.

The Therapeutic Order of Naturopathic Medicine Revisited

Naviaux makes the point that the normal health cycle requires adequate nutrient intake, waste and toxin removal, restorative sleep, and connections to nature and other people.

Particularly CDR1 maps clearly onto the first step in the therapeutic order of naturopathic medicine. These are:

  1. Identify and remove the obstacle to cure from the environment.
  2. Give the body the building blocks to heal.
  3. Stimulate the vital force.
  4. Address and support weak and damaged systems.
  5. Correct structural integrity.
  6. Address pathology with nutraceuticals.
  7. Address pathology with pharmaceuticals.
  8. Suppress symptoms with pharmaceuticals (last, and only when necessary).

But that’s all big picture. The CDR offers a fascinating peek at what might be going wrong at the cellular level, depending upon the disease process in question. I hope that as more studies are done, it’ll become increasingly clear how we might help to hit a “reset button” in each case.