Rejuvenation 2.0

By MD FACP Buckingham Robert

Rejuvenation 2.0 explains the fundamental basis for how and why our cells get old and die. It begins with vascular inflammatory free radical impingements on capillary- endothelial cell basement membranes that occur as a result of repetitive- maladaptive behaviors and lifestyle choices. The free radical impingements block the back and forth pivot

• Language: English
• Publisher: LitFire Publishing
• Release date: Sep 25, 2019
• ISBN: 9781643986685

MD FACP Buckingham Robert

I have been a practicing physician in a variety of hospital and clinic settings for 36 years. My experience in critical care, coupled with my work in noninvasive cardiac care, has provided me with unique insight into the origins of inflammation and which cells really matter in the process.The purpose for writing Hazing Aging was to allow everyone the opportunity to see what i was seeing and to make adjustments in their life based on purpose and understanding of cause and effect mechanisms.It is my intention to continue this process of sharing my insights and have written two additional books on capillary endothelia, which will be published in the next 12-16 months.In the meantime, settle in and begin the adventure of making your capillary cells healthy through anti-inflammatory living.

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Rejuvenation 2.0

How the Capillary-Cell Dance Paces and Stems Interstitial Space Sanitation and End Organ Rejuvenation to Resolve Disease, Pain and Fatigue

Copyright © 2019 by Robert Buckingham, MD, FACP

All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the publisher or author, except in the case of brief quotations embodied in critical reviews and certain other noncommercial uses permitted by copyright law.

Although every precaution has been taken to verify the accuracy of the information contained herein, the author and publisher assume no responsibility for any errors or omissions. No liability is assumed for damages that may result from the use of information contained within.

ISBN-13: 978-1-64398-668-5

Printed in the United States of America

LitFire LLC

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Rejuvenation 2.0

How the Capillary-Cell Dance Paces and Stems Interstitial Space Sanitation and End Organ Rejuvenation to Resolve Disease, Pain and Fatigue

Robert Buckingham, MD, FACP

Contents

Introduction Solving the Mystery of Chronic Inflammation

CHAPTER 1 Fatigue, Pain, and Their First Cousin-Aging

CHAPTER 2 Proinflammatory Red Flags

CHAPTER 3 Capillary-Cell Mitochondria:

More than a Motor

CHAPTER 4 The Triangular Interplay of Capillary-Cell Mitochondrial Combustion, Outer-Membrane Permeability, and Interstitial Space Inflammation

CHAPTER 5 How the Capillary–CellS Pivot and Swing: Sharing the Dance Floor with the End Organ

CHAPTER 6 The End Game of Chronic Inflammation: Interstitial-Space White Flags

CHAPTER 7 Testing for Vascular Inflammation:

The Hunt for Red Flags Before They Become White

CHAPTER 8 Therapeutics:

Rebalancing Capillary-Cell Mitochondrial Energy and Nitric Oxide Production

CHAPTER 9 The Capillary-Cell Pivot and Swing Dance: Ground Zero for Reversing Immune Suppression, Aging and Disease

Glossary

Appendix

Graph 1: Endothelial- or Capillary-Cell Inflammation/Dysfunction, Aging Acceleration, and Reversal

Graph 2: Age-Accumulative Endothelial- or Capillary-Cell Inflammation and Changes in Endothelial-Cell Markers of Function

Graph 3: Endothelial- or Capillary-Cell Inflammation and Markers of Chronic Inflammation, with Age

Graph 4: Chronic End-Organ Interstitial-Space Inflammation, Aging, and Increased Expression of Diseases

Graph 5: Effect of Endothelial- or Capillary-Cell Inflammation and Stacking of Free-Radical Inflammatory Risk Factors on Mortality, with Age

Figure 1: Anatomy of Capillary Mitochondria

Figure 2: The Movement of Hydrogen Ions (H+) from the Matrix to the Intermembrane Space of Mitochondria

Figure 3: Production of Acetyl Coenzyme A from Pyruvate in the Mitochondrial Matrix

Figure 4: Pyruvic Acid (Pyruvate) Entering the Krebs Cycle

Figure 5: Acetyl Coenzyme A Production from Fatty-Acid Beta-Oxidation

Figure 6: Glucose to Pyruvate to Acetyl Coenzyme A Metabolism and Energy Yields

Figure 7: Fluctuations in Capillary-Cell Mitochondrial Volumes from Pro- or Anti-inflammatory Influences

Figure 8: Glycolysis

Figure 9: ROS and Increased or Decreased Mitochondrial Volumes

Figure 10: The Importance of Antioxidants—SOD

Figure 11: The Damaging Effects of ROS Exhaust Coming from Excessive Mitochondrial Energy Combustion

Figure 12: Mitochondrial Reactive Oxygen Species Acting as a Cytokine

Figure 13: Heme Molecule

Figure 14: Mitochondrial Heme Production

Figure 15: The Cellular Makeup of the Blood-Brain Barrier

Figure 16: Different Capillary-Cell Outer-Membrane Morphologies

Figure 17: The Production of Nitric Oxide Gas

Figure 18: The Cause and Effect of Large-Vessel Obstructive Plaque on Nitric Oxide Production

Figure 19: Gas Exchange through the Alveolar Cell Sac

Figure 20: The Recruitment of the Immune Arsenal to Expand the Inflammatory Response and Combat Acute Breach in the Alveolar Space

Figure 21: Intestinal Absorption of Nutrients

Figure 22: Sinusoidal Capillary Cell

Figure 23: A Liver Sinusoid-A Second Look

Figure 24: Close-Up View—Liver Sinusoid

Figure 25: The Kidney Nephron

Figure 26: Cross Section—Capillary and Podocyte Cell

Figure 27: Cross Section—Skeletal Muscle

Bibliography

Introduction

Solving the Mystery of Chronic Inflammation

As a practicing physician and researcher of forty years, I have struggled in the management of fatigue and pain. These symptoms mosaic with each other yet mostly expand over time leaving a trail of disability and chronic comorbid conditions in their path. They copartner in confounding ways, duping us with different mosaics of cause or effect, making us consider one end organ’s involvement when in reality it’s a cover up for multiple end organ declines. Once treatment of pain and fatigue is initiated, the results are often disappointing, short lived or prone to relapses. Targeting treatment of different end organ diseases often does not prove much better as pain and fatigue may increase from the drugs or different treatment strategies utilized. The truth be told that unless we begin to see pain and fatigue as part of an ensemble involving chronic inflammation, we will continue to fail . With this thought in mind, Rejuvenation 2.0 will propose that connecting the chronic inflammatory dots to increases in pain and fatigue involve vascular inflammatory free radicals, interstitial space signaling feedback loops and a stalled out capillary cell dance. Spec ifically:

• increases in vascular inflammatory free radicals within interstitial spaces.

• the maturing of chronic inflammation within the interstitial space as it funnels rogue immune arsenal with its own brand of signaling cytokines.

• a stalled capillary cell outer membrane permeability pivot and mitochondrial combustion swing dance, causing excessive energy combustion and subsequent superoxide exhaust.

• loss of capillary cell mitochondrial volumes and outer membrane receptors, switches and pores

• progressively hostile cytokine signaling feedback loops within the interstitial space.

• a subsequent interstitial space signaling feedback loop coupe where capillary cell choreographed white blood cells, immunoglobulins, platelets and clotting factors are exchanged for those harboring a darker signaling feedback loop path that chronically expands chronic inflammation within the interstitial space rather than eliminating inflammatory breach to cause inflammatory contraction.

• The populating of the interstitial space of disease venues involving cancer, scarring, infections, immune complexes and hypoxia and ischemia.

When fatigue and pain are understood on the basis of chronic interstitial space inflammation, the model points to a common root cause for most diseases thereby eliminating the fragmentation that is caused by treating each disease as if it has its own unique origin. Multiple disconnected etiologies get connected to chronic interstitial space inflammation with different end organs getting different diseases based on vascular inflammatory free radical exposures, genetic vulnerability and inherent functional characteristics. In this model, chronic inflammation becomes the common cause culprit and it involves all end organs usually igniting similar rates of declines. End organ disease treatment, which is a late stage of chronic inflammation, becomes chronic inflammatory treatment which ultimately involves all end organs and their interstitial spaces.

In Rejuvenation 2.0 it is hypothesized that chronic fatigue and pain are manifestations of a maturing chronic interstitial space inflammation process that has progressed to the point where end organs have become compromised from different disease venues. These late effects of chronic interstitial space inflammation occur as a result of the earlier inability of immune arsenal entering the interstitial space to finish the job, that is to eliminate vascular inflammatory free radicals sufficiently to enable capillary cells to pivot outer membrane permeability and swing combustion to nitric oxide.

The broken capillary cell dance has escalating repercussions to its own integrity as well as that of the interstitial space and end organ. As capillary cells degenerate from the outside in and inside out due to combinations of basement membrane dysfunction and thickening and superoxide damage to membrane surfaces and DNA, their choreography of precision based immune arsenal entry into the intestinal space is blown. Instead, white blood cells, platelets and immunoglobulins enter without clear instructions about what their purpose is within the interstitial space. These rogue immune elements, through no fault of their own, release cytokines that are not purposed to remove inflammatory breach. Instead, they promote a signaling feedback loop chain reaction that chronically expands rather than contracts interstitial space inflammation. The momentum of this proinflammatory chain reaction creates its own identity to eventually impose its will on the interstitial space as it takes over signaling control. By doing so, it pirates the interstitial space, hijacks the by now disabled capillary cell outer membranes and converts mesenchymal cells to their signaling feedback loop brand. The stage is set for disease venue creation fueled by the chronic pestering and festering of vascular inflammatory free radical impingement on the interstitial space and capillary-endothelial cell basement membranes.

Vascular inflammatory free radicals are an ubiquitous group that often involve lifestyle choices and addictive behaviors. They easily co-link with each other setting up a potential vascular inflammatory free radical tsunami, which involves what we breathe, eat, how we sleep or what we think. As these free radicals enter the blood stream they persistently harass, impinge and extol end organ interstitial spaces and capillary cell basement membranes creating a perpetuating expansion of different immune arsenal towards them. It is the free radical perpetuation and the incomplete elimination within interstitial spaces that drives the blocked capillary cell dance and the escalation of proinflammatory momentum that follows

As rogue immune elements remaster the signaling feedback loop game plan of the interstitial space, the signaling feedback loop luster that was once owned by capillary cell outer membranes implodes from massive losses to outer membrane receptor, switch and pore operations and mitochondrial volumes. No longer able to generate operative feedback loops, the interstitial space becomes ripe for a rogue immune arsenal coupe and all the fall-out that follows. As long as capillary endothelial mitochondria are stuck in energy combustion, chronic interstitial space inflammation has its collective foot on the proinflammatory gas accelerator. As part of the signaling coupe, chronic inflammation takes no prisoners as its uses mesenchymal cells for its own purpose while funneling additional immune elements into the interstitial space through pirated capillary cell outer membranes. As this occurs, disease venues populate, the end organ declines and pain and fatigue escalate. The interstitial spaces of all end organs now belongs to chronic inflammation as the same coupe process has been duplicated everywhere.

With capillary cell mitochondrial combustion stuck in energy, not only is there buildup of toxic superoxide exhaust, but the counterbalancing combustion of nitric oxide is lost. Without it, capillaries don’t rejuvenate. That is, the nitric oxide gas activates infrastructure reassembly or repair, replacement, and replication of anything worn out to include organelles, nuclear telomeres, mitochondrial volumes and outer membrane receptors, switches and pores. Rejuvenation of capillary cell infrastructure drives quality assurance to future inflammatory breach removal thereby preventing chronic inflammation. More important, it helps to restore functional signaling feedback loop integrity of its outer membranes to counter rogue influences. It does this by reinstituting its choreography function thereby bringing immune arsenal into the interstitial space staging area with purposed intent to remove inflammatory breach.

Nitric oxide gas production has other important attributes as it increases blood flow and oxygen delivery to the end organ, diversifies free radical exhaust thereby enabling reconstitution of antioxidants, and becomes part of the stem and pace feedback loop signaling effect to end organ and mesenchymal cell rejuvenation. For optimal health, capillary cells must pivot and swing, interstitial spaces must be free of inflammatory free radicals and end organs must receive unimpeded on demand oxygen and nutrient.

Implied in this discussion is a much earlier recognition of chronic inflammation, its root cause and changes in proinflammatory behaviors before disease venues, fatigue and pain occur. Intervening with intentional lifestyle approaches sooner rather than later could change the trajectory of disease or even prevent it altogether. Doing so would not only eliminate the origins of most fatigue and pain but also would reduce the cost of health care delivery by postponing expensive drug treatments or risky, invasive and time consuming interventions. Wellness, which becomes the outcome to early chronic inflammatory intervention, rejuvenates while also postponing, or preventing altogether, the interventional cascades that have become so integral to the medical industrial complex.

The chronic inflammatory stakes get higher as we age. Aging in effect translates into DNA on hiatus. As our DNA gets crosslinked by different free radical consortiums, their coding effectiveness becomes unhinged. Protein synthesis, if and when it occurs, gets dicey, as production is mired with coding mistakes often resulting in poorly minted proteins that have no functional purpose. When this occurs to capillary cell outer membrane adhesion receptors, switches or pores, pseudocapillarization results and the outer membrane become prone to choreography mistakes involving misguided immune arsenal entry into the interstitial space. Similar consequences occur with capillary mitochondria, where coding errors effect inner membrane voltage gradients and hydrogen leaking into the matrix, the capacity for cytochromes to transfer electrons, as well as the integrity of other matrix operations involving beta oxidation, heme synthesis or the internal workings of the Krebs cycle.

None of these age related outcomes to malfunctioning or damaged DNA, either nuclear or mitochondrial, bodes well for capillary cell functional utility and sets the cell up for being hacked by chronic interstitial space inflammation. Age related DNA compromise makes chronic inflammatory consolidation of feedback loop signaling involving interstitial space operations that much easier.

Diligent anti-aging requires even more diligence about limiting vascular inflammatory free radical fuel. Less fuel gives capillary cells a better chance of dancing, even if the dance is less efficient due to playing with a less than full DNA deck. If the anti-inflammatory lifestyle hierarchy becomes unhinged and interstitial spaces become strewn with vascular inflammatory free radicals in the setting of compromised DNA, the chronic inflammatory processes being unleashed within intestinal spaces will be substantial.

Is there such a thing as normal aging? In the western world, the clue to how we age comes from the medicine cabinet, weight scale, refrigerator and living room. The average 70 year old may take 6 or more prescription medicines daily to treat various chronic inflammatory venues including muscle and joint pains, chronic fatigue, depression, headaches, insomnia, as well as hypertension, diabetes and lipid disorders. While this is going on, this same person will eat a preponderance of refined carbohydrates, is often 50 or more pounds overweight, spends most of their wakeful time sitting, likely suffers from increasing memory loss and has some level of obstructive sleep apnea and heartburn. In addition, hearing, vision, balance and periodontal changes have often preceded these signs and symptoms by decades. The refrigerator is often jammed with sugared and salty condiments, colas, juices, jellies, cold meats, and yogurts. In the freezer there may be ice cream, popsicles or frozen TV dinners. The pantry will harbor breads, pastries, cereals, and salted snack foods. The various alcohols of preference typically round out the display. All of this usually is fortified with a living room couch, TV, entertainment center, computer screen, tablet or smart phone. We set ourselves up to age.

Central to a lifestyle overhaul is a sobering assessment of what it means to be addicted. Addictions expand chronic inflammation as well as gateway other addictions. In its early stages, addictions can be subtle and often not recognized or denied. Of all the addictions sugar is the most lethal and confusing. With our current knowledge about various simple sugars and their additive addictive impact, food labeling has failed to catch up. In failing to label all simple sugars as sugars, package labeling has created deception about how much sugar we actually are consuming. Along with trans- fats, sugar grams are the most underreported ingredient listed on breads, snacks, and diary.

Sugar is not the only gateway addiction but it has a head start and a free pass with the early in life digestion of baby and fast food. Other addiction may soon follow in succession and include alcohol (another simple sugar) followed by tobacco and drugs (opioids, stimulants, cocaine, THC) but can also include other behaviors such as gambling, computer games, porn and shopping. All of these different addictions will take their collective toll on increasing vascular inflammatory free radicals both directly and indirectly.

So what is chronic interstitial space inflammation? A simple explanation would be a persistent cause-and-effect response to an irritant (free radical) that has the potential to monkey wrench capillary cell functional integrity to eventually involve the adjoining interstitial space and end organ. The implication to this pester and fester is that there is either too much irritant, not enough of a response to eliminate it or a combination of both. Within the interstitial space, this boils down to a persistent and excessive pestering of vascular inflammatory free radicals and the inability of incoming immune arsenal to eliminate them. The combination forms a proinflammatory chain reaction that eventually breaks down its capillary cell pivot and swing dance and tilts their mitochondria in excessive energy combustion. The subsequent buildup of superoxide free radial exhaust will decimate the capillary cell from the inside out as it assaults membrane surface and damages its nuclear and mitochondrial DNA.

Meanwhile the loss of capillary cell infrastructure is being coupled with basement membrane thickening and dissolution of signaling communication between it and the surrounding interstitial space and end organ. As capillary cells lose outer membrane receptors, pores and switches they are also losing their capacity to affect choreography of arriving immune arsenal and cytokine signaling preeminence of the interstitial space. Coupled with loss of mitochondrial volumes the weakened and ineffectual capillary cell is now threatened to capitulate the entire interstitial space as an impressive array of rogue white blood cells and other immune elements embark on their own signaling communication system that propels the interstitial space into a radically different direction of disease venues at the expense of the end organ function.

Meanwhile the capillary cell sits helpless as its outer membranes have been made vulnerable to pirating by the overwhelming cytokine signal influences of the dark and rogue immune elements harbored within the interstitial space. Coupled with converted mesenchymal cells, they unleash an unfiltered feedback loop communication system that takes full advantage of the capillary cell void. Its proinflammatory momentum will attach and disrupt membrane surfaces and cellular infrastructure through a variety of means making the interstitial space vulnerable to scarring, infections, cancer growth, rogue autoimmune complexes and pro clotting biases. As these outcomes mature, they leave a path of end organ destruction leading to aging, fatigue and pain consequences. The fuel for this destructive proinflammatory cascade begins and ends with vascular inflammatory free radicals and their descent on the interstitial space.

Making the case against this morass requires the following to occur and becomes the basis for my theory on Rejuvenation 2.0:

• Reduce vascular inflammatory free radical assault impinging the interstitial space.

• Enable the fluxing (pivoting) of capillary-cell outer membrane permeability to choreographed immune arsenal into and out of the interstitial space.

• A swinging of capillary cell mitochondrial combustion back and forth from energy to nitric oxide, thereby supplementing outer membrane energy requirements for active transport while also enabling its replenishment of infrastructure, outer membrane receptors, pores, switches and mitochondrial volumes. The capillary mitochondrial combustion swing also diversifies exhaust and enables an antioxidant rebuild. The pivot and swing cascades benefit to optimize interstitial space sanitation, nurture end organ function and feedback loop the stemming of end organ rejuvenation. In aggregate the pivot and swing insures quality assurance to future capillary cell function, interstitial space hygiene and enduring end organ functional capacity.

• The dance lessen risk to both mitochondrial and nuclear DNA by decreasing toxic free radical (superoxide) lingering and enabling the telomere rebuild through telomerase activation for nuclear chromosomal DNA.

• The dance keeps cytokine feedback loop signaling communication with its interstitial space allies the end organ and mesenchymal (helper) cells intact to ensure a seamless flow of purposed intent.

• The dance ensures that choreographed interstitial space white blood cells and other immune elements are meant to be there to eliminate interstitial space breach. Purposed white blood cells in return signal back to the capillary cell outer membranes a similar intent to provide reconnaissance and further stage breach elimination.

• The dance provides the effective refurbishment of interlocking communication channels with adjacent capillary cells as well as the intricate display of different gap junction check blocks for immune arsenal mobilization into interstitial space staging areas.

• The dance provides quality assurance to real time back and forth signaling communication with downstream large-vessel endothelia as well as further upstream venules, veins and lymph. The same can be said about distant end organs.

Lifestyle choices largely determine the success or failure of the capillary cell dance highlighted by choices that reduce vascular inflammatory free radicals. It is the continued presence of this fuel that capillary cells have no answer for and will stall out its dance. Simply said, the capillary cell dance prevents chronic inflammation but the trump card is held by vascular inflammatory free radicals.

Capillary cells, unlike other vascular endothelium that are covered by layers of smooth muscle, are specialized endothelial cells at the very end of the arterial tree that provides the interstitial space and it’s corresponding end organ what it requires from blood plasma to optimally function. They do this by having adopted specific outer membrane and basement membrane morphologies to accommodate a host of diversified end organ functions. Examples of the major end organs include the skin, heart, brain, liver, lung, and kidney. All end organs in turn have epithelial cells that have evolved sets of specialized outer membranes and infrastructure that accommodates their designated function and role in the end organ hierarchy. They are optimized on the basis of how well the interstitial space (the critically important space between the capillary and end organ cells where their business is transacted) is kept sanitized and the corresponding capillary -endothelial cell basement and outer membranes can specifically respond to their real time demands.

In spite of how diverse the capillary cell basement membranes have become, there are three constants that every capillary cell throughout the body must master to be effective. These include effective immune surveillance of the interstitial space, servicing specific end organ functional requirements, and providing feedback loop signals that stem and pace refurbishment of their own infrastructure as well as that of the end organ and mesenchymal cells. All three are essential, but effective interstitial space sanitation sets up the other two.

Within the chapters of this book, it will become clear that immune surveillance can be challenging for different end organs based on how vulnerable to chronic inflammation the interstitial space has become based on how much blood plasma is allowed to enter. The more liberal the entrance to the interstitial space, the more likely the space will be exposed to free radicals, toxins, pathogens or cancer cells. This makes immune surveillance for a given interstitial space complex and different for each end organ. For effective immune surveillance, given this varying level of potential chronic inflammatory exposures, capillary cells must gate effective choreography of entering white blood cells, immunoglobulins, platelets, complement and clotting factors based on the interstitial space context.

This means that capillary cell outer membrane adhesion receptors, pores, switches voltage gradients and gap junction channels must mediate immune arsenal choreography based on the how vulnerable the interstitial space is to proinflammatory exposures and how much support they will receive from interstitial space mesenchymal cells. When it comes to interstitial space sanitation, the combination makes for a capillary cell moving target from one end organ to the other as the pace, type and volume of immune arsenal entering into the interstitial space staging area from one end organ to the next will flux based on preexisting conditions involving its own basement membrane and the function of the end organ. Couple this with the degree to which vascular inflammatory free radicals have impinged the basement membrane and blocked the capillary cell dance, and the stage is set for an ongoing tug of war for signaling control of the interstitial space with capillary cells often falling on the short end of the stick.

Rejuvenation! provides a plausible cause and effect model on how we age and why we succumb to pain and fatigue based on the deterioration of the capillary cell dance and the interstitial space fall-out that follows. It involves a pitch battle for signaling control of all interstitial spaces and end organs, where chronic inflammation gains the upper hand over capillary cell outer membranes to control the outcomes and fate of the end organ. My hope for Rejuvenation! is twofold. First, to share in depth science based insights into this pitch battle and second, that an escape clause is provided to bypass or at least postpone these ugly outcomes.

[AUTHOR’S NOTE: Please refer to the glossary in the back of this book for a list of the clinical terminology used throughout the text.]

CHAPTER 1

Fatigue, Pain, and Their First Cousin-Aging

Throughout my forty years of medical practice, the most confounding of patient consults involve the clinical mosaics of chronic pain, fatigue or combinations of both. They co-link in so many ways that their intermingling a common trigger. The perception of pain makes fatigue worse and fatigue pushes pain thresholds lower. Both connect with most disea se venues.

On the surface of many clinical presentations, the cause of fatigue and pain can appear multi-factorial. Since they can be caused from just about any end organ dysfunction, the workup can be exhaustive, expensive and may not result in clear cut cause and effect answers. Making matters worse, the disease diagnosis and the treatment rendered may only be a stopgap, producing temporary but not satisfying relief. It is then back to the clinical-diagnostic drawing board with more tests and procedures that lead to similar cycles of temporary and incomplete benefit.

Unfortunately so much of disease treatment may come down to symptom relief, which traps both patient and health provider into the kneejerk of addicting opioid pain killers, stimulants, sleeping pills, antidepressants, muscle relaxants or combinations of all of them. None of these interventions actually cause improvement in chronic inflammation and may potentially make it worse. And when used over long periods of time most of these interventions will no doubt cause harm. So here in lies the dilemma of current medical practice. When it comes to chronic fatigue and pain we are often left with a whitewashed diagnosis, addictive treatments, serious side effects and no long term benefit to limiting root cause- chronic inflammation. As practitioners we intuitively know we have kicked the treatment can down the road, yet feel hopeless to do much about it.

Making matters worse are the complications that occur as a result of treatment decisions. The long term use of many of these prescription drugs will cause drug tolerance meaning it takes more of a given drug to get the same benefit over time. As patients complain of more pain and fatigue, and the opioid or sleeping pill doses increases, risky side effects pop up that can end up with life threatening emergencies or even death. At best, many become life-long functional addicts, being able to barely manage a job around their drug seeking behavior. And coming off these drugs or finding natural alternatives becomes next to impossible due to the tolerance, physical and psychological addiction towards them. This sets the stage for long term addiction, which often gateways the clustering of other addictions. In the meantime, chronic inflammation carries on unabated. Fatigue and pain increase and end organ disease venues sprout pushing their declining function. The end game to addiction is often not pretty with homelessness, social isolation, depression, psychosis, dementia and suicide compounding multiple end organ dysfunction.

In contrast to these dire outcomes in patient care, I have had patients with 3 vessel coronary disease that have had no surgical bypass graft or stent intervention and no chest pains. There have been others with a cancer diagnosis that have had limited conventional treatment options but their cancers have failed to show growth for years. And still others with x-ray evidence of severe degenerative arthritis but without any lower back, knee or hip pain. What gives? Why do some patients succumb to coronary disease, cancer or arthritis to die or become crippled much earlier in the disease process while others appear to go unscathed? Is it the luck of the draw or fate? Up until recently, we have shrugged these differences off as circumstances beyond our treatment control, but I beg to differ. The answer to this difference will not to be found with more narcotics, muscle relaxants, sleeping pills, or stimulants or even the latest technique for lower back surgery, bypass graft or stent procedure. Rather the answer lies in how we choose to nurture our own immune systems. I would argue that it involves lifestyle and manifests in the form of a dance.

One important point about disease treatment bears mentioning. It is a late outcome in the evolution of chronic inflammatory intent within end organ interstitial spaces. By the time traditional medicine has gotten around to a diagnosis and treatment of a disease venue, the treatment odds within the interstitial space have been stacked against success. By the time disease venues have manifested, the chronic inflammatory progression and the remastering of the interstitial space signaling systems has long since occurred. Initiating treatments without connecting them to how much immune compromise has already occurred within the interstitial space will result in short term or aborted benefits. When it comes to chronic inflammation and disease venues within interstitial spaces, the proinflamamtory signaling chain reactions that have revamped interstitial space white blood cells, immunoglobulins, platelets, clotting factors and mesenchymal cells into an organized proinflammatory amalgam has made interception and reversal very difficult. The truth be told, chronic inflammatory intervenetion should occur before signs and symptoms involving end organ interstitial space disease venues have evolved.

Mitigating chronic inflammation, sooner rather than later, becomes the wellness answer and involves the systematic rooting out of the vascular inflammatory free radical fuel that triggers the onset of chronic interstitial space inflammation. The sooner this gets accomplished the better. The sooner that anti-inflammatory behaviors are adopted, the less likely that disease venues will strike, even in those genetically vulnerable. The difference between those with asymptomatic triple vessel coronary disease, degenerative arthritis and inactive cancer to those toiling in perpetual distress with chest pain, shortness of breath, pain killers and chemotherapy, could boil down to how effective our body’s immune system has been enabled to mitigate their progression and the anti-inflammatory behavior skill set that has been adopted to support it. While it is reasonable to urgently alleviate and treat chest pain, disabling arthritis pain, and emerging cancer with every medical weapon available, avoiding the chronic inflammatory elephant in the room will limit the long term effectiveness of all such treatments.

The trick in this discussion is identifying and eliminating vascular inflammatory free radicals before they do harm. Lifestyle choices become a teaching tool and the center piece to this awareness. Making adjustments early in life makes disease prevention easier and lessens the risk for chronic pain and fatigue. When implemented, the fuel that tends to expand chronic inflammation in all interstitial spaces dries up. This chain reacts benefit as optimal immune homeostasis within interstitial spaces instills its sanitation thereby providing a positive feedback loop overture to capillary cell outer membranes and mitochondria. Pain and fatigue will self- limit as its root cause-interstitial space disease and subsequent end organ dysfunction can’t find traction. In this context, preventing or treating pain and fatigue is not about waiting for chronic inflammation to cause a disease venue, but rather preempting the process all together.

For any meaningful result, behavioral adjustments must universally favor and all in approach to vascular inflammatory free radical reduction. Implementing some anti-inflammatory behaviors, while ignoring others, will backfire and will leave the chronic inflammatory door cracked open. In the cracked open door scenario, chronic inflammation will take what it can from the open door and take advantage of interstitial space vulnerabilities that could be unique to any given end organ. Besides attempting to eliminate all dietary simple sugars, alcohol, cigarettes, and addictions, stress should be modified, sleep deprivation minimized and an exercise program instituted. Paying only lip service to any of these will keep the chronic inflammatory door cracked open.

Other refinements to anti-inflammatory strategies can also help. Tai chi for balance, yoga or back stretches for low back pain and meditation can help mitigate preexisting conditions. Losing weight to maintain an optimal BMI (body mass index), treating sleep apnea, or taking medicines to control blood sugar, blood pressure or LDL cholesterol may also be necessary. The point being made is that chronic inflammation is many splendored, multidimensional and a moving target. The more successful the lifestyle intervention, the more that pain and fatigue will remit and the less medications will be required to treat disease. In the chronic inflammatory model, the emergence of pain or fatigue becomes a red flag to increasing chronic inflammation and the remastering of interstitial space signaling feedback loops from a compromised immune system.

Outside- In Inflammatory Mediators: The Incendiary Fuel for Chronic Inflammation

Outside-in inflammation is usually caused by what we inhale, smell, taste, inject, touch or ingest. They are known as outside in or first- line inflammatory mediators and can be composed of different types of vascular inflammatory free radicals. It is not uncommon for some of these inflammatory mediators once in the bloodstream to additionally impact sleep hygiene, increase stress levels, increase insulin resistance and gateway addictions, thereby doubling down free radical impingements within interstitial spaces. What many of these different vascular inflammatory free radicals have in common is their predilection for capillary and endothelial cell basement membrane attachment and subsequent mobilization of an immune response towards them. If this impingement somehow becomes chronic, the vascular inflammatory free radical pester and fester effect will ignite a chronic inflammatory response within interstitial spaces.

Outside-in inflammatory mediators can cluster, attract and stack to each other to accelerate inflammation. In this manner they are also known as vascular inflammatory free radical seeds. They seed or fuel inflammation by initially pushing the body’s immune arsenal towards them to expand the inflammatory response. If they cannot be completely cleared, the response become chronic and increasingly subject to errors in immune judgement due to the increasing inability of capillary-endothelial cells to deliver a purposed –choreographed immune arsenal response against them. The chronic vascular inflammatory free radical festering freezes the capillary cell pivot and swing dance, pushes superoxide (ROS-reactive oxygen species) damage to membrane surfaces and DNA, and induces basement membrane dysfunction by thickening it from chronic inflammatory residues that include assorted vascular inflammatory free radicals, monocyte- foam cells, clotting factors and other assorted white blood cells. As proinflammatory cascades garner interstitial space momentum signaling cytokine feedback loops within the interstitial space become vulnerable for takeover from rogue immune elements that proceed to hijack control from the weakened capillary cell.

Inside- Out Inflammatory Mediators:

Our Innate Response to Inflammation that can Betray

The real damage that is caused from vascular inflammatory free radical seeding to basement membranes and interstitial spaces comes from what they attract towards their attachment and subsequently does not get removed. Instead of the incoming immune arsenal (also known as inside out inflammatory mediators) contracting inflammation by eliminating the free radical, it does the opposite and chronically expands the inflammatory response. The chronic inflammatory cascade, which is caused by too much free radical impingement or not enough precision from arriving immune arsenal, not only thickens and denigrates basement membrane function, but chain reacts proinflammatoruy cascades that adversely affect the capillary cell dance. As the dance stalls out in mitochondrial combustion of energy, the stage is set for superoxide ROS poisoning of capillary cell membranes, DNA and subsequent function. Included in the inside out inflammatory mediators are many different inflammatory proteins produced by the liver, white blood cells, cytokines, immunoglobulins, clotting factors, complement and platelets.

Initially, and with optimal interstitial space homeostasis and sanitation, second-line inflammatory mediators enter the interstitial space staging area by choreographed invitation from capillary cells. Their purpose is to isolate, neutralize and eliminate the free radical seed. If they don’t, interstitial space inflammation on the basement membrane festers and can degenerate into an array of inflammatory debris consisting of white blood cells, platelets, cytokines and monocytes (foam cells). In larger arterial vessels, the initial insult is known as a fatty streak, but depending on the type of free radical incursion, there can be different variations.

As the chronic inflammatory response on the basement membrane and/or some other locale in the interstitial space matures, the amalgam sets the stage for a blocked capillary cell dance, internal superoxide damage, pseudocapillarization of its outer membranes and the subsequent loss of choreography of immune arsenal entrance into the interstitial space staging area. Pseudocapillarization enables the funneling of confused immune arsenal into the interstitial space, which subsequently unleash cytokine signals that encumber inflammatory breach elimination while stoking additional inept immune arsenal arrivals. The proinflammatory cytokine signaling momentum will eventually organize as it seizes control of the disabled capillary cell outer membranes and the interstitial space feedback loop signaling apparatus.

The inflammation it generates blocks the capillary cell dance to keep their mitochondria in persistent energy combustion. This one –two chronic inflammatory punch to capillary endothelia in effect produces an outside-in and then inside- out gutting of the cell pushing increased superoxide exhaust, DNA silencing from cross linkage, diminished nitric oxide driven rejuvenation and subsequent pseudocapillarization of outer membranes and reduction of mitochondrial reserves. As this occurs, capillary cell choreography vanishes such that their outer membranes become a funnel for waves of useless immune arsenal into the interstitial space. This group is easily distracted and vulnerable to cross signaling from rogue influences that have already penetrated the interstitial space thereby creating wayward signaling momentum. This cytokine signaling momentum runs counter to capillary cell choreography and its allies and eventually garners enough momentum to control the interstitial space, pirate capillary cell outer membranes and set interstitial space agendas that run counter to end organ function.

The Inflammatory Matrix: The Organizing of Chronic Inflammation

When the chronic inflammatory matrix has secured signaling feedback loop control within the interstitial space of any end organ, the intent of the interstitial space changes from nurturing and supporting end organ function to stoking chronic inflammatory agendas. For this proinflammatory sequence to occur, it must include the following milieu:

• Abundant vascular inflammatory free radical fuel within the interstitial space and an ineffective immune arsenal response towards their removal

• A stalled capillary cell dance that breaks down capillary cell infrastructure, outer membranes and mitochondria via outside in (basement membrane thickening) and inside out (superoxide) damage.

• An increasing array of funneled and confused white blood cells and other immune remnants into the interstitial space that lack precision towards removal of inflammatory breach.

• A disparaging cytokine signaling apparatus within the interstitial space, which is nurtured by these ineffectual immune arsenal, that expands inflammation rather than removes inflammatory breach.

• The subsequent hijacking of the disabled capillary cell outer membranes by these rogue cytokines to signal increasing momentum to the funneling of inept immune weaponry into the interstitial space.

• As chronic inflammation expands and masterminds signaling control of the interstitial space it begins to organize intent.

When chronic inflammation escalates to these levels, it has organized enough cytokine signaling control to manifest purpose. As rogue white blood cells have duped mesenchymal cells to join the resistance, cells of the end organ have become increasingly isolated and ignored by the dysfunctional capillary endothelia. With the interstitial space signaling apparatus in lock down, the inflammatory matrix can now yield to the next stage of chronic inflammatory hierarchy, the interstitial space anti-organ.

The Anti-Organ: The Outcome of Exploding Chronic Inflammatory Momentum

With the maturing of chronic interstitial space inflammation, the anti-organ can emerge to implement disease venues. With a consortium of signaling feedback loops at its disposal and coupled with the disintegration of endothelial -capillary cell function, the anti-organ can aggregate proinflammatory momentum to a tainted interstitial space for the induction of diseases. In this context, one disease may trigger additional diseases but all work in favor of chronic inflammation and against the end organ. The onslaught can begin with the formation of scar tissue, but can escalate to include the unleashing of rogue autoimmune complexes, the precipitation of proclotting aggregates and the hiding and proliferation of different infectious agents and cancer cells. As they proliferate and the end organ declines, fatigue, pain and aging accelerate. They become the interstitial space white flags of surrender as one signaling feedback loop system meant to facilitate interstitial space sanitation and nurture end organ function (capillary cell choreography) is exchanged for one that exploits the interstitial space at the expense of the end organ.

The implication is that the emerging chronic inflammatory anti-organ will completely disrupt all signaling connections that involve interstitial space homeostasis and end organ function. It starts insidiously with vascular inflammatory free radicals within the interstitial space, and the fumbling of their removal, progresses to the development of the inflammatory matrix and capitulates with the anti-organ and disease multiples. As chronic inflammation matures its signaling cytokine feedback loops harness control over the swath of interstitial space operations. The disabled capillary cell endothelia can only passively watch as their outer membranes and inept infrastructure aid and abet the process. With chronic inflammation in control of the interstitial space, there is no capillary cell choreography as it has been replaced with the anti-organ brand of funneled immune arsenal. Hence there is no capability of eliminating inflammatory breach. There is no rejuvenation as capillary cell nitric oxide combustion has been shut down and in many instances DNA irreversibly damaged. There is also no stemming or pacing of mesenchymal or end organ rejuvenation either. Instead capillary cells and their allies have become reactive zombies to chronic inflammatory purpose. The anti-organ has succeeded in wiping out any avenue of immune retaliation.

As the end organ declines and interstitial space disease venues escalate, aging, fatigue and pain accelerate. The anti-organ will mastermind full signaling control of the interstitial space. As it does, capillary cells atrophy or die as does the end organ. The ultimate success of the anti-organ is to commit suicide by killing off its own lifeblood. Before it does, it exhausts every metabolic venue to its favor.

Unlike most end organs, which require abundant oxygen delivery to augment their function, the anti-organ and the disease venues it creates, are much more oxygen flexible. Many disease venues may require minimal or no oxygen to prosper thereby giving them a distinct advantage over the compromised end organ. In the setting of increasing disease venue momentum, having the interstitial space become increasingly oxygen deprived reduces end organ function while possibly increasing anti-organ reserves, as many of its venues will capably utilize fermentation for energy.

Chronic inflammation involving one interstitial space of one end organ is almost never the case. Instead it may give the appearance of involving one end organ but it actually has pushed its way into all end organs. Making matters worse, chronic Inflammation appearing as a disease venue in one end organ, may present in a different end organ as a different disease venue or spread of disease venues. The anti-organ effect is not only potentially lethal as it manifests its mosaic in one end organ but invites disease venue diversity to different end organs based on their unique vulnerabilities.

The Staging of Chronic Inflammation:

A Proposed Pathway of How it All Comes Together

The bullets below offer a theory of how chronic inflammation takes down the capillary-cell dance and establishes control of the interstitial space:

• Outside-in inflammatory mediators, also known as first-line inflammatory mediators or vascular inflammatory–free radicals, penetrate interstitial spaces utilizing a variety of techniques including diffusion, facilitated diffusion and inherent lipid solubility. In a few situations, they may hitch a free vagabond ride on actively transported proteins such as albumen. Different examples of a diversified group of free radicals include carbon monoxide gas, inhaled or smoked particulates, ingested toxins or their bi products (alcohol, drugs), small particle LDL or VLDL cholesterol, triglycerides, homocysteine, non HDL cholesterol, and lipo (a). In aggregate they will utilize different tricks, and often in stealth, on epithelial and endothelial/ capillary cell outer membranes to mobilize into interstitial spaces and attach to different surfaces, including endothelial and capillary cell basement membranes.

• Once attached, they become fodder for an immune arsenal (second line-inside out) response towards their attachment. Different free radicals will derange endothelial basement membranes in different ways based on how their attachment disrupts membrane function, what kind of immune arsenal responds to it, and whether or not it gets eliminated from the membrane surface. If not completely removed or allowed to fester, the attached free radical and the immune response it generates will alter membrane function by disabling receptors, scramble responses, silence membrane proteins, impinge infrastructure mechanics, and induce a chronic inflammatory response that consists of free radical residuals, foam cells (fat laden macrophages), white blood cells, and clot proteins. The composite creates a fatty streak that eventually leads to basement membrane thickening. The process will involve arterial endothelium from the largest of arteries to capillaries.

• When the vascular inflammatory free radical- immune arsenal attachment festers, it becomes a rogue force and works against the capillary cell dance, interstitial space sanitation and end organ function. Instead of eliminating the attachment to cause inflammatory contraction and a pivot of capillary cell outer membrane permeability towards less immune arsenal mobilization into the interstitial space , the festering perpetuates expansion of immune arsenal entry and blocks the permeability shift of capillary-endothelial cell outer membranes.

• This pushes an ongoing requirement for calcium ion release and ATP production from adjacent mitochondria, as they labor to provide energy for outer membrane active transport of additional immune arsenal constituents. As mitochondria are energy combustion overworked and are not permitted to swing combustion to nitric oxide, rejuvenation (also known as 3 -R rejuvenation-repair, replacement, replication)of membrane receptors, pores, switches as well as cell and mitochondrial infrastructure does not occur. As parts wear out and are not replaced, cracks develop in capillary-endothelial cell function which include outer membrane sequencing choreography of immune arsenal and mitochondrial energy production reserve as outer membranes pseudocapillarize and mitochondrial volumes shrink (from fission and pore suicide).

• Without capillary endothelial cell outer membranes able to respond properly to interstitial space signals or effectively choreograph immune into the interstitial space or for mitochondria to supply enough energy to support active transport, capillary and endothelial cell outer membranes enable the funneling of mistake prone and non- purposed immune arsenal into the interstitial space. As their numbers increase, they provide signaling momentum for even more inflammatory expansion as their released cytokines (lymphokines) pirate capillary cell outer membranes and accelerate a rogue brand of immune arsenal into the interstitial space. Once pirating occurs, capillary endothelium become passive players to interstitial space signaling and chronic inflammation (as a matrix) has begun to organize intent.

• As capillary cell outer membranes pseudocapillarize many membrane functions fall apart as mitochondrial energy is drained from their support. Besides the dissolution of active transport by budded vesicles and transcellular gated channels, reduced energy support will effect switch activation as well as impact osmotic/oncotic