Remodeling
Altered tissue healing in inflammatory environments
The human body has an amazing capacity to heal. However, it is generally accepted among medical research and medical experts that the ability to heal becomes more difficult as we age. It is assumed that as the body ages, the body suffers a gradual degeneration of health which impairs our ability to heal. Additionally, when we do heal, the healing process is not as robust or efficient as it would be for a younger body. Healing may take longer. Scar tissue may form. In the case of a musculoskeletal injury, flexibility may be lost, pain can persist. The injury may require additional surgery or require longer periods of rehabilitation. The injury could become a debilitating injury permanently.
“It becomes evident that excessive activation or insufficient control of complement activation on host cells can cause an immune imbalance that may fuel a vicious cycle between complement, inflammatory cells, and tissue damage that exacerbates clinical complications.”
\immune inflam complem pathophys 2013.pdf
So, we do accept that the healing process is more challenging as we age. However, have we investigated exactly why this is the case? And, if by identifying the causal mechanisms of dysfunctional healing, is it conceivable to improve or correct the healing process so that we do not lose function or suffer continuing symptoms and disability permanently? We propose that the answers to these questions have already been discovered and documented. Our intent is to analyze this information and reach conclusions that will provide the basis to construct treatments that will capitalize upon the power of the human body to heal.
“For most species, the aging process is a progressive accumulation of damage, loss of the physiological functions of cells and organs, and reduced physical activity. The radical theory of aging is a proposed mechanism that was advocated by Harman.[55] This theory hypothesizes that ROS (reactive oxygen species) generation and increased oxidative stress lead to progressive macromolecular oxidative damage and dysfunction, which induces aging and age-related diseases.[56]
\Curcumin molec mech full 2014.pdf
Diseases of time
We must begin with redefining long-held beliefs about human physiology. We now know a lot more about disease processes that are involved in “aging.” It is important to recognize and accept that the phenomenon of aging itself is inextricably tied to chronic disease. More precisely, aging is the incremental degeneration of health due to an escalating, systemic chronic inflammatory environment. This environment can be described as encompassing both the entire body’s physiology as a system and the mechanisms of disease and healing occurring at the cell level, the tissue microenvironment.
Aside from human evolutional development like maturation and reproductive function, are there specific tissues and functions that truly deteriorate due to the natural aging process as the body matures? Possibly, but all other categories attributed to aging should be reviewed. When the accepted characteristics of aging are viewed from the perspective of chronic inflammatory disease, every characteristic currently attributed to aging, such as degenerative disease, metabolic dysfunction, pain, hormone imbalance, energy loss, immune deficiency,all are inextricably tied to chronic inflammation. As we will see, the existence of a chronic state of inflammation residing in the body as whole inflicts a state of self-injury. This self-injury, over time, accumulates and causes subsequent injury. An escalating state of chronic injury-response (the body continuously attempting to heal injury (real or “perceived”) continues. This escalating systemic state not only limits healing, but also reduces the ability of the body to function properly. Tissues actually undergo a process where the replacement tissue is modified (remodeled) to better survive within this inflammatory environment. The mechanisms of chronic degenerative disease processes must be reconsidered. The conclusion, diseases of aging and the subsequent difficulty in healing, the remodeling of tissue, resulting loss of function; these are not diseases or consequences of aging, they are actually “diseases of time.”
An escalating, systemic, chronic inflammatory environment
Whether due to diet, environment or evolutionary programming,* without exception, every person harbors the mechanisms of chronic inflammatory disease. In fact, due to the very functions of chronic inflammation, the body is continually injured by this chronic process. Repeated injury (at the cell level) results in dysfunctional healing. This process, due to its chronic cyclic characteristics can only escalate over time. Over many years or decades, it is reasonable to understand that by harboring continuous systemic injury, impacting every cell in the body, the body has no choice but to adapt to this injurious environment. Adaptive healing is required to protect the tissue from the chronic injury of the inflammatory environment. This process has nothing to do with aging. This process of adaptive healing can be called “remodeling.” It is a function of years of continuous, incremental injury. and subsequent dysfunctional healing, which in turn, generates additional, escalating injury.
Hepatic IR (ischemia-reperfusion injury) is a particularly interesting model as its main pathological consequence, i.e., the massive loss of hepatocytes during reperfusion, originates from a complex crosstalk between ER stress, oxidative stress, and inflammation during ischemia. Hypoxia induces indeed a considerable overgeneration of ROS [78], in turn (i) directly stimulating the (at least partially) NF-kB-dependent transactivation of various proinflammatory mediators [53] and (ii) promoting protein unfolding and hence triggering the ER stress response (as documented by the activation of XBP1 and ATF6 in the parenchyma of livers undergoing IR) [44,45].”
\cell death signaling liver 2013.pdf
What makes chronic disease “chronic?”
When and why does a chronic disease disease become “chronic?” Recent research has revealed that all chronic inflammatory diseases, at the cell level, share a multitude of common traits. When investigated, it becomes very apparent that all chronic diseases, even cancers, exhibit many common characteristics. At the cell level, the body is continually reacting and adapting to perceived threats or injury. These processes are automatic. Each cell possesses sensory apparatus to monitor its environment and react to signaling presented to the cell. Such signaling may be a specific protein that encounters the cell surface. It may be an accumulation of lipids around the cell. It may be an erosion of the extra-cellular matrix surrounding the cell. It may be any variety of changes in the cell’s environment that may generate cell stress. It may be surprising to some that the inflammatory process actually causes injury to cells, even healthy cells. Cancer, for example, was only recently defined as an “inflammatory disease.” Cancers can be considered as a more permanent conversion of an inflammatory tissue microenvironment. This “injured” environment presents a continuous, escalating cycle of cell stress and inflammatory injury response. These responses can actually cause additional injury to cells which in turn, escalates this process. Recognized “hallmarks” of cancers (proliferation, mobility, invasion, survival, etc.) are inextricably tied to the consequences of a chronic disease microenvironment. Cancer recurrence following treatment also exhibits the same hallmarks, only at a more aggressive pace. Amazingly, this important “discovery” is controversial in the medical community an continues to be debated.
“Metabolic, infectious, and tumor cell-intrinsic noxae (irritants) can all evoke the endoplasmic reticulum (ER) stress response in tumor cells, which is critical for tumor cell growth and cancer progression.
”Endoplasmic_Reticulum_Stress_Pro-Inflammatory.doc, PNAS, 2011
“…inflammation functions at all three stages of tumor development: initiation, progression and metastasis.”
\Executive Summary of Inflammation and Cancer Think Tank.pdf, National Cancer Institute, 2005
“Inflammation is a response to acute tissue damage, whether resulting from physical injury, ischemic injury, infection, exposure to toxins, or other types of trauma. It can play a role in tumor suppression by stimulating an antitumor immune response, but more often it appears to stimulate tumor development. Epidemiologic and clinical research indicates an increased risk of certain cancers in the setting of chronic inflammation.”
\Executive Summary of Inflammation and Cancer Think Tank.pdf, National Cancer Institute, 2005
“Evidence in the peer-reviewed literature suggested that chronic prostatic inflammation may be involved in the development and progression of chronic prostatic disease, such as BPH and PCa, although there is still no evidence of a causal relation.”
\Epstein_Criteria_Insignificant.doc
Yet it has become evident that complement not only acts as a sensor of pathogens but also recognizes diseased and damaged host cells, and it closely collaborates with other immune and defense systems to eliminate potential danger (1, 2). This interplay serves as a vital triage system that tailors the immune response according to the threat level.”
\immune inflam complem pathophys 2013.pdf
Cell signaling – the mechanisms of disease at its most basic level
Each cell within a tissue microenvironment exists within a dynamic system of signaling. The cell senses its surrounding environment and reacts to it. It is direct and automatic. Changes in the microenvironment affects the behavior of the cell. Each cell in return emits its own signaling mechanisms into the surrounding environment. These signals will affect the behavior of surrounding cells. Signaling in sufficient quantities, by a sufficient quantity of cells, will communicate the existence of even local injurious events systemically throughout the body. Understanding the dynamics of cell signaling has become the focal point of research to discover the mechanisms of disease and healing. Defining and mapping cell signaling has presented the opportunity to understand the mechanisms of disease at its most basic levels. This knowledge has provided the opportunity to understand disease from a brand new perspective, to break the cycle of chronic inflammatory disease.
“The NF-κB (Nuclear Factor-kappaB) family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways.”
\NFkB signaling complexity 2013.pdf
Remodeling
It must recognized that when a chronic inflammatory tissue environment exists over a long period of time (years!) there will be consequences. You must expect that tissue healing will be impaired. Re-injury of tissue which occurs in an inflammatory environment will inevitably cause the modification of tissue. Tissue healing will not be as efficient as it would be in a normal tissue environment. In fact, tissue will be continuously modified to better survive as its environment undergoes escalating inflammation and injury. The inflammatory tissue environment actually exhibits dramatically different characteristics in comparison to that of normal healthy cells. When we look closely how these tissues are remodeled, it presents significant understanding of how the chronic inflammatory environment, when allowed to persist, can degrade the physiology of the body, both locally and systemically. We it may be a dangerous misrepresentation to label these processes diseases of “aging” when they actually are the signatures of chronic inflammatory disease.
How does an injury from a single event become a chronic injury? In the tissue microenvironment, the cell must sense that it is undergoing a form of stress or injury, real or perceived. The cell’s environment is presenting a continuous or even escalating stress or injury, or signaling of stress or injury. A dysfunction in the healing of that injury which occurs within an inflammatory state, can create a chronic injured state and accordingly, inflammatory signaling. In the context of dysfunctional healing, what exactly is the cause of the “self-injury” to develop into a chronic injury? This must be due to the remodeling of the tissue when repaired or healed. When taking into account all the types of tissue that can be injured, it becomes very apparent that a chronic inflammatory environment, when allowed to continue, actually robs the body of function, degrades the quality of life. This is not aging. This is chronic disease and the consequences of its persistence.
“Medial artery calcification (MAC) is a characteristic feature of diabetes. MAC represents a concentric calcification that proceeds via matrix vesicle-nucleated mineralization accompanied with apatitic calcium phosphate deposits in the arterial tunica media in the absence of atheroma and neointima. Multiple factors contribute to the induction and progression of diabetic MAC including inflammation, oxidative stress, adiposity, insulin resistance, advanced glycation end-products, and hyperphosphatemia. Osteoblast-like cells form in the vessel wall from vascular smooth muscle cells and multipotent vascular mesenchymal progenitors. These mineralizing cells as well as the recruitment of undifferentiated progenitors to the osteochondrocyte lineage play a critical role in the calcification process… Currently, no therapy is available to reverse vascular calcification.”
\medial artery calcif mech diabetes 2014.pdf
Consequences
If this is an misunderstanding within medicine, then what are the consequences of the misunderstanding? More importantly, what opportunities are presented to improving health care if this is true? If it is generally accepted that healing will not be as complete with older patients, have we not already “lowered the bar,” accepted a lesser standard of care? Consider the years of cost and suffering for millions of patients, simply because we have universally lowered expectations of outcomes?
Redefining chronic “inflammatory” disease
The term “inflammation” was created to describe the redness and warming surrounding the area of an injury. The assumption was that the body was increasing blood flow to the injury to deliver oxygen and nutrients to the cells, deliver the resources required for the cells to repair the injury. The “inflammatory response” was automatic with the intent to heal the wound and protect against potential infection (“immune response”). We have since learned that the inflammatory response is much more complex mechanism and occurs in a variety of “injury” environments. Investigation of how these processes develop to create of chronic cell injury or cell stress, provides the insight to understanding chronic diseases. The origins of disease, of chronic inflammatory disease, reside at the cell level, how the cell responds to its immediate environment and to the perceived stress generated. The cascade of signaling resulting from cell stress creates a complex, dynamic array of signaling, exponential in response. The signaling pathways generated by cell stress have been identified in detail. These pathways provide insight into the origins and consequences of cell signaling. They also provide the mechanisms, the origins, of signaling that create a chronic environment of disease.
“The mechanisms of loss of beta cell mass is different in type 1 and type 2 diabetes, but the metabolic outcome is the same, and beta cell ER stress is a feature of both diseases.”
\alpha cells survival pancreatic 2015.pdf
Renewal
Is it possible to reverse the consequences of years of chronic inflammation? Is it possible to correct dysfunctional, remodeled tissues? What if with each case of chronic inflammation or inflammatory disease, we were able to both reduce inflammation (return the tissue microenvironment to a healthy state) and regenerate healthy tissue (heal) to replace dysfunctional remodeled tissue? The implications could be far-reaching.
An injury that took place years ago continues to create intense pain. Medical diagnostic procedures have resulted that no injury can be detected. Injuries of this type are actually very common. Current medical practice has no explanation and accordingly, no opportunity for curative treatment other than physical therapy when or if appropriate. Afterwards, if pain or disability persists, physicians can only prescribe pain medication. Of course, this is not a solution and almost invariably creates a more dangerous condition for the patient with a diminishing quality of life. All tests within the current standard of care result that the tissue is healthy and normal. The patient, in frustration, must live with pain and disability.
“Under normal physiologic conditions, bone-resorbing osteoclasts and bone-forming osteoblasts are tightly coupled and regulated to ensure the proper balance, such that there is no net change in bone mass. However, inflammation perturbs normal bone homeostasis. . . “Cytokines are central to the pathogenesis of inflammation-induced bone loss and contribute to the uncoupling of osteoclast-mediated bone resorption and osteoblast-mediated bone formation, thereby disrupting normal remodeling.”
\remodeling bone rheumatic 2016.pdf
Spine injury is a classic case. Thousands of patients must rely on pain medications and accept the consequences of those medications. We propose that the original injury created an extended period of chronic inflammation and re-injury, which perpetuated the inflammatory environment. In the example of spine injury, the spine has critical importance as its structure and its role to protect the central nervous system while providing flexible structural support for the body. When injured, attempts to heal the spine and surrounding tissues within a chronic inflammatory state, can result in the remodeling of tissue. Tissues remodeled can include bone and connective tissues, and also include nerves and blood vessels. Due its critical role, the spine and surrounding remodeled tissues can become hypersensitive to movement to protect from any perceived or potential added injury. Remodeling of vessels and other tissues, such as muscle, can result in intense pain and spasm which may be caused by only a subtle movement. Current diagnostic testing methods reveal fail to discover or identify injury.
All physicians are familiar with the use of statins to reduce or counteract inflammation. They are also aware of the revelations that long-term use of statins can damage tissues and over time can create a more dangerous disease state. We do not advocate the use of statins for long-term control of inflammation. Whenever a foreign agent is introduced to inhibit the body’s natural process of healing, the body will automatically take action to overcome the the actions of the invader drug. Actions may be to inhibit or over-express a pathway, or a number of pathways of response.
Chronic use of pain killers presents a list of negative side effects. It is also an unfortunate consequence of the use of narcotics that, while they may be necessary, they will tend to exasperate the injured microenvironment by allowing additional physical injury. The additional injury occurs in an inflammatory tissue environment. Remodeling is escalated, potentially causing additional pain and injury.
Inflammatory response, or more aptly, injury response, creates an environment whereby repair and regrowth of tissues is remodeled. Remodeling, as its prime objective, is meant to protect the tissue or organ that is being repaired from a chronic inflammatory injury environment and potential externally generated injury (e.g. movement, temperature extremes, ischemia, energy expenditure, etc.). Conversely, by eliminating local and systemic inflammation while tissue is healing, the tissue can be repaired more to its original, healthy state and function. Research indicates that prior injuries, perhaps years previous, have experienced a state of continuous, escalating remodeling. Such remodeling has created a more enhanced inflammatory environment which creates more inflammation, tissue injury and additional remodeling. To correct years of this escalating cycle, it may be required that, similar to weight training, where muscle tissue is “broken-down” to be re-grown with larger or stronger cell structure. Tissue remodeled by chronic inflammation could be gradually “re-injured” so that repair and regrowth can occur in an inflammation-free environment. We have the capability to dramatically reduce inflammation during re-injury and repair. Similar to the weight-training example, recovery from injuries years in the making could take an extended period of time to correct.