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Inflammation Part 3: Other Perspectives on Inflammation – Causes & Consequences

Current research has introduced other perspectives on both the causes and consequences of inflammation, including more global perspectives. The previous articles on inflammation focused largely on inflammation due to traumatic injury to soft tissue:

Inflammation Part 1: Inflammation, Joint Injuries & Anti-Inflammatory Drugs

Inflammation Part 2: Inflammation, RICE, & Chinese Medicine

However inflammation can be present in many diseases, and there appears to be an underlying mechanism within the seeming wide variability in presentations.

Whether an injury or disease is caused by trauma, infection, auto-immune problems, communicable or non-communicable disease, stress and psychological factors or environmental factors, the same cascade of inflammation – virtually the same general physiological response – is observed:

  • An increase in blood supply to the affected area.
  • An increase in white blood cells in the affected tissues.
  • An increase in phagocytic activity in order to remove the dead tissues and the offending agent.
  • A subsequent reduction in the above three mechanisms resulting in healing

Rethinking Inflammation

Before we examine global ideas about inflammation, let’s stay for a moment with the idea of local trauma to tissue take a look at an interesting viewpoint on  the causes of inflammation. Srdan V. Stankov from the Pasteur Institute in Novi Sad, Serbia, questions the classic five signs of inflammation: redness (rubor), heat (calor), swelling (tumor), pain (dolor), and loss of function (functio-laesa). Stankov feels that this definition fails to explain well-established empirical facts, particularly the extent of the osmotic pressure and temperature variations within the inflamed tissue.[1]

Stankov goes on to postulate that inflammation is a direct consequence of a tissue injury that shifts the metabolic balance towards catabolism. Manifestations of enhanced catabolism in the course of an inflammatory process may be proteolysis (a hydrolysis reaction of peptide bonds in which proteins breakdown into smaller peptides and/or into individual amino acid residues), diminution of cellular space volume or diminished oxidative metabolism. Therefore inflammation may be a pathological process, and not the defensive reaction proposed by other researchers, whereas the anti-inflammatory response that ensues after inflammation reaches its climax, is a true defensive response.

The principle cause of inflammation in this model is then mechanical pressure – blunt trauma, the presence of foreign bodies, vibrations, or even chronic pressure of low intensity (compression – remember R.I.C.E.). This means that the basic mechanism causing inflammation by pressure is most probably through tissue hypoxia. Exposed to pressure, the volume of tissue water, important nutritional components carried by tissue fluids (which cannot be compressed), and oxygen are squeezed out of the tissue. Upon cessation of pressure, the tissue remains shrunk for a certain period of time, and while the tissue remains shrunken there is significantly diminished oxygen content. Hypoxia may then generate inflammatory changes, through the direct impairment of mitochondrially mediated anabolic (cell building) processes. This creates a metabolic shift towards catabolism (cell tearing down).

Stankov goes on to postulate that the second most important inflammagenic factor is cold (remember the icing part of R.I.C.E.). He says that cooling is capable of causing inflammatory edema. This is partially due the fact that heat is necessary for stimulation of anabolism. Following this line of thinking and research, Stankov goes on to make three extraordinary comments that may be of particular interest to practitioners of traditional Chinese medicine:

  1. The common belief that exposure to cold at least predisposes one to inflammatory conditions of infectious or noninfectious nature is therefore fully substantiated.
  2. This brings up the obvious therapeutic possibility – the addition of heat to inflamed tissues.
  3. For unknown reasons therapists have been reluctant to use this technique (heat) for treatment of acute inflammatory conditions.

The idea that cold can cause infectious disease and can be treated with warmth is fully in line with the idea of “Cold Damage” as presented Zhong Zhang Jing in the Shang Han Lun (Treatise on Cold Damage), and with the fundamental importance of preserving Yang.

It is important to remember that in Chinese medicine there is no concept of “inflammation,” yet there are therapies and herbs that treat what Western medicine identifies as inflammation. Stankov’s analysis shows the danger of assuming that heat, redness and pain are inflammation, and the danger of carelessly mixing Western and Eastern concepts.

Inflammation as a Global Universal Response

New thinking about inflammation is that it begins when the body senses “danger,” in the form of infection, trauma, ischemia, physical threats, chemical exposure, or other challenges. Non-antigenic stimuli may be perceived as “danger” and initiate an inflammatory response. These influences include trauma such as radiation, ischaemia, toxin exposure, and even psychological stress. These factors may induce inflammation by various mechanisms, including activation of neuroendocrine pathways (as seen with emotional stress and depression), or through the up-regulation of “stress” pathways which stimulate inflammatory signaling, Environmental toxins and chemicals (e.g., pesticide residues, additives, preservatives) may also induce inflammatory activity factors).[2]

Exposure to long-term environmental noise, likely via the associated alterations in microbiome–gut–brain axis status, up-regulates oxidative stress and systemic low-grade inflammation, which may underlie epithelial barrier deficits in the intestine and brain, and may thus be an environmental risk factor for Early Onset Alzheimer’s disease in vulnerable individuals.[3]

Inflammation triggers a whole body response by activation of many different feedback loops. The sympathetic nervous system (SNS) is activated while the parasympathetic nervous system (PNS) and the hypothalamic-pituitary-adrenal (HPA) axis generally inhibit inflammatory responses. However, chronic activation of the stress response systems can lead to excessive immune cell activity and promote systemic inflammation. Therefore the body reacts as an integrated system. Hence, the prevailing siloed view of diseases being independent of each other and therefore needing to be managed by discrete specific interventions is no longer tenable, and as experience shows has largely limited success.[4]

This explains why disturbances in one part of the system can cause cascading effects, causing multiple interactions and crossover-effects. This can help explain seemingly separate co-morbidities like coronary artery disease, cerebral artery problems, obesity, cardiac irregularities, diabetes, depression, osteoarthritis and early aging.

These last two are particularly interesting. Traditionally “wear and tear” on joints is thought to be the cause of osteoarthritis leading to loss of cartilage, however, it now seems that Osteoarthritis (OA) may in fact be a chronic disease and results from damage to the articular cartilage induced by a complex interplay of genetic, metabolic, biochemical, and biomechanical factors followed by activation of inflammatory response involving the interaction of the cartilage, subchondral bone, and synovium[5] There is increasing evidence that synovial inflammation plays a critical role in the symptoms and structural progression of OA. Importantly, synovitis has been shown to correlate with symptom severity, rate of cartilage degeneration and osteophytosis (formation of bone spurs).[6]

In relation to aging, chronic low-grade inflammation in multiple organs can lead to functional decline even in the absence of specific diseases. Chronic inflammation also seems to be a consequence of the steady accumulation of cellular damage and the failure to clear the breakdown products of cellular catabolism. In addition, life-long exposure to antigens causes progressive activation of innate immune cells, further increasing pro-inflammatory cytokine release and chronic low-grade inflammation.[7]

The above analysis of an accumulation of damage leading to aging and decline makes me think of not only of Chinese medicine’s interconnected, integrated, whole-body approach t0 health, but also of the Daoist physician Ge Hong (283 – 343), whose “system” of nourishing life and cultivating longevity involves first learning to avoid “wounding” the body through stress, intemperate living, and having unbounded desires – factors that chronically activate the body’s stress response systems and cause stasis and congestion.

Wounding occurs when our thought is troubled with things for which we lack talent; also when we force ourselves to do lifting without the requisite strength. Sadness, decrepitude, uneasiness and torment are wounds, as is also excessive joy. Constant covetousness wounds, as do long conversations and the telling of pointless stories. Wasting time abed, archery contests, drunkenness and its vomitings, lying down after a heavy meal, getting breathless from running, shouts of joy and weepings, abstention from sexual intercourse – all these are wounds. When wounds have been accumulated to the point of exhaustion, death soon ensues.[8]

Ge Hong goes on to say that we don’t notice these things as being wounds to the body when they occur, but as they accumulate, they shorten one’s life and damage one’s health. Therefore people must learn how to nourish life and regulate the body.

Notes

[1] “Definition of Inflammation, Causes of Inflammation and Possible Anti-inflammatory Strategies”, Srdan V. Stankov* The Open Inflammation Journal, 2012, 5, 1-9.

[2] “Inflammation–Nature’s Way to Efficiently Respond to All Types of Challenges: Implications for Understanding and Managing “the Epidemic” of Chronic Diseases.”Jeanette M. Bennett, Glenn Reeves, George E. Billman, and Joachim P. Sturmberg. Frontiers in Medicine: November 2018, Volume 5, Article 316.

[3] “Environmental noise stress disturbs commensal microbiota homeostasis and induces oxi-inflammmation and AD-like neuropathology through epithelial barrier disruption in the EOAD mouse model.”Huimin Chi, Wa Cao, et al. Journal of Neuroinflammation (2021) 18:9 https://doi.org/10.1186/s12974-020-02053-3

[4] “Inflammation–Nature’s Way to Efficiently Respond to All Types of Challenges: Implications for Understanding and Managing “the Epidemic” of Chronic Diseases.”Jeanette M. Bennett, Glenn Reeves, George E. Billman, and Joachim P. Sturmberg. Frontiers in Medicine: November 2018, Volume 5, Article 316.

[5] Haseeb A, Haqqi TM. “Immunopathogenesis of osteoarthritis” Clinical Immunology. 2013 Mar;146(3):185-96. doi: 10.1016/j.clim.2012.12.011. Epub 2013 Jan 6. PMID: 23360836; PMCID: PMC4015466.

[6] Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51(2):249-257. doi:10.1016/j.bone.2012.02.012

[7] “Inflammation–Nature’s Way to Efficiently Respond to All Types of Challenges: Implications for Understanding and Managing “the Epidemic” of Chronic Diseases.”

[8] Alchemy, Medicine and Religion in the China of AD 320: The Nei Pien of Ko Hung. James R. Ware (trans and ed) (New York: Dover Publications, 1966) pp. 223-24.