English Corner: Oral NaHCO3, M2 macrophages, Carbon dioxide and inflammation

Oral NaHCO3, M2 macrophages, Carbon dioxide and inflammation
Target points
- Understanding the action of bicarbonate (NaHCO3) on inflammation and immune system (1)
- Interaction of macrophages with the redox signals, reprogramming the environment in health and disease: Redox Control of Inflammation by Macrophages (sensing mechanisms), induced by NaHCO3 (2-3)
- Protective effects of CO2 on immunosuppressive system, mediated by the splenic nerve (new anti-inflammatory pathway), with the help of the chemical messenger acetylcholine (4)
- Carbon dioxide has antioxidant effects, and many other stabilizing actions. (5)
Article
Until recently the “reason” wasn’t quite clear why and particularly how sodium bicarbonate could dampen inflammation, namely by people suffering from arthritis. But not only inflammation.
The process is not directly linked with the acidosis but with a shift from regulatory T-cells: "The shift from inflammatory to an anti-inflammatory profile is happening everywhere," Dr. O'Connor says. "We saw it in the kidneys, we saw it in the spleen, now we see it in the peripheral blood."
Dr. Paul O'Connor is a renal physiologist in the MCG Department of Physiology at Augusta University and the study's corresponding author.
 Drinking baking soda, the scientists think, tells the spleen -- which is part of the immune system, acting then as a sensor, and where some white blood cells (like macrophages) are stored -- to go easy on the immune response. (5) The communication, which occurs with the help of the chemical messenger acetylcholine, is obtained with 2 gr oral NaHCO3, in water diluted.
"We think the cholinergic (acetylcholine) signals that we know mediate this anti-inflammatory response aren't coming directly from the vagal nerve innervating the spleen, but from the mesothelial cells that form these connections to the spleen," O'Connor says. (…)
"You are not really turning anything off or on, you are just pushing it toward one side by giving an anti-inflammatory stimulus," he says, in this case, away from harmful inflammation. "It's potentially a really safe way to treat inflammatory disease."
Comment (LucH): “You are not really turning anything off”. Yes, indeed, provided you stop the taking of oral NaHCO3, at a deferred moment (thus in cure). Taking baking soda when there is an excessive reaction, alright, so that to calm down, thus not on a continuous way. (…)
Acetylcholine (ACh) is the chief neurotransmitter of the [Vous devez être inscrit et connecté pour voir ce lien] nervous system, the part of the autonomic nervous system, that contracts [Vous devez être inscrit et connecté pour voir ce lien], dilates blood vessels, increases bodily secretions, and slows heart rate. ACh can stimulate a response or block a response and thus can have excitatory or inhibitory effects ^{[Vous devez être inscrit et connecté pour voir ce lien]}.
Other cells besides neurons use this transmitter ACh.
Baking soda also interact with acidic ingredients like lemon juice or cocoa in cakes and other baked goods to help the batter expand and, along with heat from the oven, to rise.
Comment (LucH): I want to underline the production of CO2, contributing to the expand and the heating of a cake in the oven. It’s not just an affair about acidifying less or not. The effect produced by CO2 should have been explored / explained more in depth! Inspired by RP, once again
That’s what I’m trying to do in the next chapter: Carbon dioxide and progesterone as protective agents.
Sources and References: See next post.

Sources and References
1. Bicarbonate NaH3O et inflammation
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=> NaHCO3 can promote a powerful anti-inflammatory response by shaping macrophage differentiation or by modulating various macrophage functions to restore health.
In humans (and other higher animals), macrophage M1 gives essentially an inhibiting response and M2 give a heal-type response.  
=> The importance of macrophage M1/inhibit and M2/heal imbalances in various disease or protective processes being clear, immunologists and clinicians are interested in how they might therapeutically intervene to shape macrophage differentiation or modulate various macrophage functions to restore health.
The “Fork in the Road” that macrophages take in making either M1/inhibit or M2/heal-type responses define “immunity” throughout the animal kingdom. In all animals, M1/inhibit-type responses are the primary host defense, and M2/heal-type responses help repair and replace lost or effete tissue to maintain host homeostasis. In humans (and other higher animals), macrophage M1/inhibit or M2/heal-type responses necessarily direct T (and B) cells/adaptive immunity to make Th1 or Th2-like responses. Thus, whether acting directly or indirectly, which “fork” macrophages take is the central controlling element that promotes health (as in pathogen control or wound repair) or impedes health (as in atherosclerosis, autoimmunity, or cancer).
Explained in another way, caricatured: M1 will induce a TH1 type response. M2 will induce a TH2 type response. TH1 will be pro-inflammatory (defense). TH2 will be anti-inflammatory (healing and reconstruction mode).
Comment: A balance must be found (pendulum effect), according to the situation (defense or building up mode).
2. Repolarization of macrophages
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Extract (translated):
The effect of bicarbonate is due to (re)-polarization of M1 / M2 macrophages and to the increase of FOXP3 + CD4 + regulatory T cells (Tregs). These T cells regulate the immune response (hence the name "T regulatory cells" in English).
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doi: [Vous devez être inscrit et connecté pour voir ce lien]
Interaction of macrophages with the redox signals, reprogramming the environment in health and disease: Redox Control of Inflammation in Macrophages
Note: Macrophages have specific tasks, with remarkable plasticity (adaptation), enabling them to respond to the disturbances in tissue homeostasis. Once macrophages reach the site of injury (or the targeted organ in the case of an immune reaction), sensing mechanisms operates, involving NO and / or ROS. (3)
3. Redox Systems Modulate and Determine the Macrophage Phagocyte Function
See [Vous devez être inscrit et connecté pour voir ce lien], the mechanisms how this interaction is controlled by and how it controls redox signals. Same source as 3. The NO/ROS redox biology not only helps to eliminate pathogens or to kill tumor cells but also shapes other aspects of macrophage biology.
4. Bicarbonate Sodium, carbon dioxide and the phenotype of lymphocytes
The anti-inflammatory baking soda effect is mediated by the splenic nerve
-) Bicarbonate Sodium, CO2 and inhibiting effect of macrophage M1
Sodium bicarbonate impacts the phenotypes of the macrophages. We found that sodium bicarbonate effects on variation of macrophage responses. Macrophages are known to play pivotal roles in host-defense through inflammation via both innate and acquired immune systems (…)
=> When modulating M1, lymphocytes TH1 inhibit / moderate the adaptive response: immunological and inflammatory reactions are moderate, in response to bacterial infection, tumor development, cytokines and so on. Thus sodium bicarbonate would be a regulatory factor of NO and TNFα production; its concentration has a crucial role in macrophage activation.
DOI:[Vous devez être inscrit et connecté pour voir ce lien]
-) Carbon Monoxide Regulates Macrophage Differentiation and Polarization toward the M2 Phenotype through Upregulation of Heme Oxygenase 1
doi: [Vous devez être inscrit et connecté pour voir ce lien] 2021
Monocytes differentiate into macrophages, including pro-inflammatory (M1) and anti-inflammatory (M2) cells, in response to environmental signals.
These results suggest that the abundantly produced CO in activated macrophages enhances proliferation, differentiation, and polarization toward M2. It will probably help clear apoptotic cells, resolve inflammation, and promote wound healing and tissue remodeling.
-) Elevated CO2 is anti-inflammatory and immunosuppressive
We hypothesized that immune cells such as monocytes and macrophages have developed a sensing mechanism allowing them to detect and respond to different levels of CO2 and adjust their inflammatory response accordingly.
Elevated CO2 is anti-inflammatory and immunosuppressive, which can have either detrimental or beneficial effects for patients depending on the underlying pathological condition. However, the sensing and signaling mechanisms underpinning this response remain poorly understood.
Source: Carbon Dioxide Sensing by Immune Cells Occurs through Carbonic Anhydrase 2–Dependent Changes in Intracellular pH 
[Vous devez être inscrit et connecté pour voir ce lien]  2022 
-) Modulating M1, lymphocytes TH1 inhibit / moderate the adaptive response: immunological and inflammatory reactions
Modulating M1 (macrophage) with sodium bicarbonate
The activating mechanism remains unknown, limiting NaHCO3’s therapeutic application. First-time evidence of NaHCO3-anti-inflammatory effect is splenic nerve-mediated, bringing an anti-inflammatory polarization.
DOI : [Vous devez être inscrit et connecté pour voir ce lien] 
The immunomodulatory effect of oral NaHCO₃ is mediated by the splenic nerve: multivariate impact revealed by artificial neural networks. JNI 2024
The NaHCO3 treatment did not impact T-helper, CD11bc + CD38 + , CD4- T cells, and CD4-FoxP3 + T cells. Spleen denervation increased CD11bc + CD38 + cells and suppressed CD4-FoxP3 + T cells. In rats.
Summary
In summary, in the SH animals, treatment with oral NaHCO₃ in comparison with H₂O increased M2-like macrophages, Tregs, and Tregs/M1-like ratio while decreased M1-like macrophages, the granularity index of CD11bc/FSC^high, and M1-like/M2-like ratio. Other cells were not affected including T-helper, CD11bc + CD38 + cells, CD4-T cells, and CD4-FoxP3 + T cells. In SD animals, the comparison of these immunological markers between H₂O and NaHCO₃ remained largely unchanged (Table [Vous devez être inscrit et connecté pour voir ce lien], Figs. [Vous devez être inscrit et connecté pour voir ce lien], and [Vous devez être inscrit et connecté pour voir ce lien]). Lastly, the interaction between surgery and treatment suggests an independent immunomodulatory effect induced by spleen denervation (Table [Vous devez être inscrit et connecté pour voir ce lien]).
Note (LucH): In humans (and other higher animals), macrophage M1 gives essentially an inhibiting response and M2 give a heal-type response. In all animals, M1/inhibit-type responses are the primary host defense, and M2/heal-type responses help repair and replace lost or effete tissue to maintain host homeostasis.
Note 2: We shouldn’t stay too long in only one zone (depressed or excited effect) to enhance an adaptative response of the immune system.
-) Oral NaHCO3 activates a splenic anti-inflammatory pathway
Oral NaHCO3 activates a splenic anti-inflammatory pathway; evidence cholinergic signals are transmitted via mesothelial cells.
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doi: 10.4049/jimmunol.1701605 2018  
-. Drinking baking soda could be an inexpensive, safe way to combat autoimmune disease
A daily dose of baking soda may help reduce the destructive inflammation of autoimmune diseases like rheumatoid arthritis, scientists report. 
Explanation of the process on this link. See abstract beneath.
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Source: DOI [Vous devez être inscrit et connecté pour voir ce lien]  JNI 2024.
Abstract
We tested the hypothesis that 'Oral NaHCO₃ intake stimulates splenic anti-inflammatory pathways. Following oral NaHCO₃ loading, macrophage polarization was shifted from predominantly M1 (inflammatory) to M2 (regulatory) phenotypes and FOXP3⁺CD4⁺ T-lymphocytes increased in the spleen, blood and kidneys of rats. Similar anti-inflammatory changes in macrophage polarization were observed in the blood of human subjects following NaHCO₃ ingestion. 
Our data indicate that oral NaHCO₃ activates a splenic anti-inflammatory pathway and provides evidence that the signals that mediate this response are transmitted to the spleen via a novel neuronal like function of mesothelial cells.

Carbon dioxide and progesterone as protective agents
Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
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Excerpt 1
Carbon dioxide protects cells in many ways. By bonding to amino groups, it can inhibit the glycation of proteins during oxidative stress, and it can limit the formation of free radicals in the blood; inhibition of xanthine oxidase is one mechanism (Shibata, et al., 1998). It can reduce inflammation caused by endotoxin/LPS, by lowering the formation of tumor necrosis factor, IL-8 and other promoters of inflammation (Shimotakahara, et al., 2008). It protects mitochondria (Lavani, et al., 2007), maintaining (or even increasing) their ability to respire during stress.
Excerpt 2
“In general, lactic acid in the blood can be taken as a sign of defective respiration, since the breakdown of glucose to lactic acid increases to make up for deficient oxidative energy production. Normal aging seems to involve a tendency toward excess lactic acid-production, and age-pigment is known to activate the process. Eliminating respiratory toxins (such as unsaturated oils, estrogenic and anti-thyroid substances, lead, and excess iron) is the most obvious first step to take when there is excess lactic acid formation. Carbon dioxide supplements have been shown experimentally to reduce residual lactate production.
Excerpt 3
“We know that glucose can be metabolized into pyruvic acid, which, in the presence of oxygen, can be metabolized into carbon dioxide. Without oxygen, pyruvic acid can be converted into lactic acid. The production of lactic acid tends to increase the pH inside the cell, and its excretion can lower the pH outside the cell.
The decrease of carbon dioxide that generally accompanies increased lactic acid, corresponds to increased intracellular pH. Carbon dioxide binds to many types of protein, for example by forming carbamino groups, changing the protein conformation, as well as its electrical properties, such as its isoelectric point. With increased pH, cell proteins become more strongly ionized, tending to separate, allowing water to enter the spaces, in the same way a gel swells in an alkaline solution.
The Bohr-Haldane effect describes the fact that hemoglobin releases oxygen in the presence of carbon dioxide, and releases carbon dioxide in the presence of oxygen. When oxygen is too abundant, it makes breathing more difficult, and one of its effects is to cause carbon dioxide to be lost rapidly. At high altitude, more carbon dioxide is retained, and this makes cellular respiration more efficient. (…)
All of the typical causes of cataracts, aging, poisons, and radiation, decrease the formation of carbon dioxide, and tend to increase the formation of lactic acid. Lactic acid excess is typically found in eyes with cataracts.
The electrical charge on the structural proteins will tend to increase in the presence of lactic acid or the deficiency of carbon dioxide, and the increase of charge will tend to increase the absorption of water.
Useful links
-) Protective CO2 and aging
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-) The biology of carbon dioxide
Video 1.17’ Dr Ray PEAT PhD. Interviewed by Dr Bud Weiss.
-) Blocking Tissue Destruction
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Excerpt 1
If we can understand the mechanisms of atrophy, and how to retard or to block tissue destruction, then we can restore the balance to a degree which might allow regeneration to occur, even if we don't clearly understand the mechanisms of growth.
Excerpt 2
Vitamin A's effect on the skin opposes that of estrogen.4 There are several mechanisms that could account for this. Vitamin A is used in the formation of steroids, and since the skin is a major site of steroid metabolism, vitamin A might help to maintain the level of the anti-catabolic steroids. A deficiency of vitamin A causes excessive release of the lysosomal enzymes, acid hydrolases, resulting in tissue catabolism.5 Also, vitamin A is necessary for the proper differentiation of cells in skin and other membranes. A deficiency tends to cause an increased rate of cell division, with the production of abnormal cells, and a substitution of keratinized cells for other types. Estrogen also promotes keratinization and speeds cell division.
Excerpt 3
Prolactin (which is promoted by estrogen, and inhibited by progesterone) increases with stress and with age. It probably affects every tissue, but it seems to have its greatest effects on the secretory membranes.
Excerpt 4
Progesterone, which is the most abundant hormone of pregnancy, has both anti-inflammatory and anesthetic actions, which would be of obvious benefit in arthritis. No toxic side effects have been found for progesterone or pregnenolone.
Pregnenolone is the material the body uses to form either progesterone or DHEA. Besides many people [have seen their] arthritis improved with only thyroid supplementation. I know of several other people who used progesterone topically for inflamed tendons, damaged cartilage, or other inflammations. (…)
We often hear that "there is no cure for arthritis, because the causes are not known." If the cause is an imbalance in the normal hormones of adaptation and resistance, then eliminating the cause by restoring balance will produce a true cure.

Carbon dioxide as component of the life process
“The end product of respiration is carbon dioxide, and it is an essential component of the life process” – Kate DEERING.
Kate DEERING is an exercise physiologist, personal trainer, nutritional and lifestyle coach, not a medical doctor. 
See her book “How to Heal Your Metabolism”   See link beneath.
Note: Top 3 of the read posts on this forum.
Kate Deering says:
Things that will help increase cellular respiration and help heal your metabolism:
- Decrease polyunsaturated fats (PUFA): PUFA has adverse effect on mitochondrial cells (unstable and oxidant) and binds to thyroid transporters. 
- Decrease phytoestrogens (soy). They increase FFA, which inhibit the thyroid function.
- Increase saturated fats, if used properly and adequately.
- Eat the right types of carbohydrates (sugars) [according to your capacity / tolerance to spare lost energy].
- Eat the right type of protein. Consuming easily digestible proteins like organic beef broth, gelatin, white fish, eggs, dairy and shellfish help support the liver and thyroid.  Increase thyroid hormone increases mitochondria respiration and increases CO2 production.
- Increasing Carbon dioxide (C02). C02 helps increase cellular respiration.  You can increase your C02 levels by living at high altitudes, bag breathing, ingesting or bathing in baking soda and increasing your intake of carbonated water.
- The right exercise.  Stressful exercise increases mitochondrial damage.  Long duration cardio is incredibly stressful to the body. According to Dr. Ray Peat “concentric” weight training is actually restorative to the cells mitochondria.  This means lifting with a load and relaxing without a load.  Burst training (short burst of exercise followed by rest) is also supportive of a healthy metabolism.
- Get enough sunlight.
- Get more Sleep (restorative function).
Note: To optimize energy production sugars should be used while awake and fats should be used while asleep.
- Stop dieting. 
- Reduce all other toxins. This includes processed foods, trans-fats, high fructose corn syrup, additives, preservatives, carrageenan, hormones, anti-biotics, drugs, alcohol, environmental toxins, fluoride, pesticides, herbicides, mercury, radiation, etc.  All toxins will disrupt and interfere with proper cell function.  All toxins will lower cellular respiration.
Source: How to heal your metabolism – Cellular Respiration (book)
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